U.S. patent application number 11/705683 was filed with the patent office on 2008-01-31 for functionally selective alpha2c adrenoreceptor agonists.
This patent application is currently assigned to Schering Corporation and Pharmacopeia, Inc.. Invention is credited to Robert G. Aslanian, Christopher W. Boyce, Jianhua Chao, Salem Fevrier, Chia-Yu Huang, Bo Liang, Rong-Qiang Liu, Huagang Lu, Pietro Mangiaracina, Kevin D. McCormick, Neng-Yang Shih, Younong Yu.
Application Number | 20080027100 11/705683 |
Document ID | / |
Family ID | 39705239 |
Filed Date | 2008-01-31 |
United States Patent
Application |
20080027100 |
Kind Code |
A1 |
McCormick; Kevin D. ; et
al. |
January 31, 2008 |
Functionally selective alpha2C adrenoreceptor agonists
Abstract
In its many embodiments, the present invention provides a novel
class of indolines as inhibitors of .alpha.2C adrenergic receptor
agonists, methods of preparing such compounds, pharmaceutical
compositions containing one or more such compounds, methods of
preparing pharmaceutical formulations comprising one or more such
compounds, and methods of treatment, prevention, inhibition, or
amelioration of one or more conditions associated with the
.alpha.2C adrenergic receptors using such compounds or
pharmaceutical compositions.
Inventors: |
McCormick; Kevin D.;
(Basking Ridge, NJ) ; Boyce; Christopher W.;
(Flemington, NJ) ; Shih; Neng-Yang; (Warren,
NJ) ; Huang; Chia-Yu; (West Windsor, NJ) ;
Aslanian; Robert G.; (Rockaway, NJ) ; Chao;
Jianhua; (Pompton Lakes, NJ) ; Fevrier; Salem;
(Cranford, NJ) ; Liang; Bo; (Lawrenceville,
NJ) ; Lu; Huagang; (Plainsboro, NJ) ;
Mangiaracina; Pietro; (Monsey, NY) ; Liu;
Rong-Qiang; (Kendall Park, NJ) ; Yu; Younong;
(Scotch Plains, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation and
Pharmacopeia, Inc.
|
Family ID: |
39705239 |
Appl. No.: |
11/705683 |
Filed: |
February 13, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11508458 |
Aug 23, 2006 |
|
|
|
11705683 |
Feb 13, 2007 |
|
|
|
60711398 |
Aug 25, 2005 |
|
|
|
Current U.S.
Class: |
514/314 ;
435/375; 514/397; 546/165; 548/312.1 |
Current CPC
Class: |
C07D 403/06 20130101;
C07D 417/14 20130101; A61P 11/02 20180101; A61P 13/00 20180101;
C07D 403/02 20130101; A61P 1/12 20180101; C07D 413/14 20130101;
A61P 9/00 20180101; A61P 31/10 20180101; C07D 407/14 20130101; A61P
27/14 20180101; C07D 405/14 20130101; A61P 25/06 20180101; A61P
37/00 20180101; A61P 25/18 20180101; A61P 25/22 20180101; C07D
401/14 20130101; A61P 25/24 20180101; C07D 409/14 20130101; A61P
25/02 20180101; A61P 25/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/314 ;
435/375; 514/397; 546/165; 548/312.1 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; A61K 31/4709 20060101 A61K031/4709; A61P 1/12
20060101 A61P001/12; A61P 13/00 20060101 A61P013/00; A61P 25/00
20060101 A61P025/00; A61P 25/06 20060101 A61P025/06; A61P 25/18
20060101 A61P025/18; A61P 25/24 20060101 A61P025/24; A61P 27/14
20060101 A61P027/14; A61P 37/00 20060101 A61P037/00; A61P 9/00
20060101 A61P009/00; C07D 215/00 20060101 C07D215/00; C07D 403/06
20060101 C07D403/06; C12N 5/00 20060101 C12N005/00 |
Claims
1. A compound represented by the structural ##STR412## or a
pharmaceutically acceptable salt, ester, solvate or prodrug
thereof, wherein: A is a 5-membered heterocyclic ring containing
1-3 heteroatoms, and is optionally substituted with at least one
R.sup.5 and/or 1 or 2 (.dbd.O) groups; J.sup.1, J.sup.2, and
J.sup.3 are independently --N--, --N(O)-- or --C(R.sup.2)--;
J.sup.4 is C or N; J.sup.5 is --C(R.sup.6)-- or --N(R.sup.6)-- is a
single or double bond; R.sup.1 is selected from the group
consisting of --[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qN(R.sup.7)YR.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qNR.sup.7R.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qOYR.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, and --P(.dbd.O)R.sup.8.sub.2;
Y is selected from the group consisting of a bond, --C(.dbd.O)--,
--C(.dbd.O)NR.sup.7--, --C(.dbd.O)O--,
--C(.dbd.O)-[C(R.sup.a)(R.sup.b)].sub.n--O--C(.dbd.O)--,
--C(.dbd.O)N(R.sup.c)--O--, --C(.dbd.NR.sup.7)--,
--C(.dbd.NOR.sup.7)--, --C(.dbd.NR.sup.7)NR.sup.7--,
--C(.dbd.NR.sup.7)NR.sup.70--, --S(O).sub.p--,
--SO.sub.2NR.sup.7--, and --C(.dbd.S)NR.sup.7--; wherein R.sup.a
and R.sup.b are independently selected from the group consisting of
H, alkyl, alkoxy, and halo, and R.sup.c is H or alkyl; R.sup.2 is
independently selected from the group consisting of H, --OH, halo,
--CN, --NO.sub.2, --S(O).sub.pR.sup.7, --NR.sup.7R.sup.7',
--(CH.sub.2).sub.qYR.sup.7', --(CH.sub.2).sub.qN(R.sup.7)YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7',
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'), --P(.dbd.O)NR.sup.7R.sup.7', and
--P(.dbd.O)R.sup.8.sub.2, and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5; R.sup.3 is
independently selected from the group consisting of H, halo and
(.dbd.O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5, provided that
when w is 3, no more than 2 of the R.sup.3 groups may be (.dbd.O);
R.sup.4 is independently selected from the group consisting of H,
--CN and halo, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7, and --S(O).sub.pR.sup.7, and
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents and/or 1 or 2 (.dbd.O) groups; R.sup.6 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents and/or 1 or 2 (.dbd.O) groups, and --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.7, --C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7
and --SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected
from the group consisting of H and alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, cyclocyclenyl, cyclocyclenylalkyl,
aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclenyl,
heterocyclenylalkyl, heteroaryl, and heteroarylalkyl, each of which
is optionally substituted one or more times by R.sup.12; R.sup.7'
is independently selected from the group consisting of H and alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cyclocyclenyl,
cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heterocyclenyl, heterocyclenylalkyl, heteroaryl,
and heteroarylalkyl, each of which is optionally substituted one or
more times by R.sup.12; R.sup.7 and R.sup.7' together with the
nitrogen atom to which they are attached form a 3- to 8-membered
heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition
to the N atom, 1 or 2 additional hetero atoms selected from the
group consisting of O, N, --N(R.sup.9)-- and S, wherein said rings
are optionally substituted by 1 to 5 independently selected R.sup.5
moieties and/or 1 or 2 (.dbd.O) groups, R.sup.8 is independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, alkoxy, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11 substituents and/or 1
or 2 (.dbd.O) groups; R.sup.9 is independently selected from the
group consisting of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11
substituents and/or 1 or 2 (.dbd.O) groups; and R.sup.10 is
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--S(O).sub.pR.sup.11 substituents and/or 1 or 2 (.dbd.O) groups;
R.sup.11 is a moiety independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which
is optionally substituted by at least one substituent independently
selected from the group consisting of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11').sub.2, and --S(O).sub.pR.sup.11' and/or 1 or 2
(.dbd.O) groups; R.sup.11' is independently selected from the group
consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R.sup.12 is
independently selected from selected from the group consisting of
H, halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--S(O).sub.pR.sup.11' and/or 1 or 2 (.dbd.O) groups, and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy,
heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy,
heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy,
heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy
groups, each of which in turn is optionally substituted by at least
once by a substituent selected from the group consisting of H,
alkyl, haloalkyl, halo, --OH, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted cycloalkoxy,
optionally substituted heteroaryloxy, optionally substituted
heterocyclenyloxy, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--S(O).sub.pR.sup.11 and/or 1 or 2 (.dbd.O) groups, wherein said
optionally substituted alkoxy, aryloxy, optionally substituted
cycloalkoxy, optionally substituted heteroaryloxy, and
heterocyclenyloxy when substituted are substituted one or more
times by R.sup.11; m is 1-5; n is independently 1-3; p is
independently 0-2; q is independently 0-6; and w is 1-3; with the
following provisos: (a) if J.sup.1-J.sup.3 are --C(H)--, R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qOYR.sup.7', q is 0, and A is
unsubstituted imidazolyl, then Y is other than a bond; (b) if
J.sup.1-J.sup.3 are --C(H)--, R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7', q is 0, and A is
unsubstituted imidazolyl, then Y is other than a bond; (c) if
J.sup.4 is N, then J.sup.5 is --C(R.sup.6)--; (d) if J.sup.4 is C,
then J.sup.5 is --N(R.sup.6)-- and (e) if A is unsubstituted
imidazolyl, R.sup.1 is --[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7', q is
0, Y is --C(.dbd.O)-- or --C(.dbd.O)O--, then R.sup.7 is other than
H or alkyl (f) if R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7', q=0, and
Y=--C(.dbd.NR.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, or --C(.dbd.NR.sup.7)N(R.sup.c)O--,
then R.sup.7 and R.sup.7' may not be taken together to form a 3- to
8-membered heterocyclyl, heterocyclenyl or heteroaryl ring; and (g)
if R.sup.1 is --[C(R.sup.a)(R.sup.b)].sub.qN(R.sup.7)YR.sup.7' or
--[C(R.sup.a)(R.sup.b)].sub.qNR.sup.7R.sup.7' and q=0, then R.sup.7
and R.sup.7' may not be taken together to form a 3- to 8-membered
heterocyclyl, heterocyclenyl or heteroaryl ring.
2. The compound of claim 1, wherein: J.sup.1-J.sup.3 are each
--C(R.sup.2)--; A is a 5-membered heteroaryl or heterocyclenyl ring
selected from the group consisting of imidazole, imadazoline, and
oxazoline, each of which is optionally substituted by at least one
R.sup.5 and/or 1 or 2 (.dbd.O) groups; R.sup.1 is selected from the
group consisting of --(CH.sub.2).sub.qYR.sup.7',
--(CH.sub.2).sub.qN(R.sup.7)YR.sup.7',
--(CH.sub.2).sub.qN(YR.sup.7)(YR.sup.7'),
--(CH.sub.2).sub.qNR.sup.7R.sup.7', --(CH.sub.2).sub.qOYR.sup.7',
and --(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7'; Y is selected from
the group consisting of a bond, --C(.dbd.O)--,
--C(.dbd.O)NR.sup.7--, --C(.dbd.O)O--,
--C(.dbd.O)-[C(R.sup.a)(R.sup.b)].sub.n--O--C(.dbd.O)--,
--C(.dbd.O)N(R.sup.c)--O--, --C(.dbd.NR.sup.7)--,
--C(.dbd.NOR.sup.7)--, --C(.dbd.NR.sup.7)NR.sup.7--,
--C(.dbd.NR.sup.7)NR.sup.70--, --S(O).sub.p--,
--SO.sub.2NR.sup.7--, and --C(.dbd.S)NR.sup.7--; R.sup.2 is
independently selected from the group consisting of H, --OH, halo,
--CN, --NO.sub.2, --SR.sup.7, --NR.sup.7R.sup.7',
--(CH.sub.2).sub.qYR.sup.7', --(CH.sub.2).sub.qN(R.sup.7)YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7', and
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7', and alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl groups optionally substituted with at least one
R.sup.5; R.sup.3 is independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5; R.sup.4 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; R.sup.5 is independently selected from
the group consisting of H, halo, --OH, --CN, --NO.sub.2,
--NR.sup.7R.sup.7', and --SR.sup.7, and alkyl, alkoxy, alkenyl,
alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7 substituents; R.sup.6
is independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cyclocyclenyl, cyclocyclenylalkyl, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclenyl,
heterocyclenylalkyl, heteroaryl, heteroarylalkyl, each of which is
optionally substituted one or more times by R.sup.12; R.sup.7' is
independently selected from the group consisting of H and alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cyclocyclenyl,
cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heterocyclenyl, heterocyclenylalkyl, heteroaryl,
heteroarylalkyl, each of which is optionally substituted one or
more times by R.sup.12; or R.sup.7 and R.sup.7' together with the
nitrogen atom to which they are attached form a 3- to 8-membered
heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition
to the N atom, 1 or 2 additional hetero atoms selected from the
group consisting of O, N, --N(R.sup.9)-- and S, wherein said rings
are optionally substituted by 1 to 5 independently selected R.sup.5
moieties, R.sup.8 is independently selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heterocyclyl, heteroaryl, and heteroarylalkyl groups, each of which
is optionally substituted with at least one of halo, alkoxy, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.9 is independently selected from the group
consisting of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.10 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
and heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11),
and --SR.sup.11 substituents; R.sup.11 is a moiety independently
selected from the group consisting of H and alkyl, alkoxy, alkenyl,
alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl, each of which is optionally substituted by at
least one substituent independently selected from the group
consisting of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2,
and --S(O).sub.pR.sup.11; R.sup.11' is independently selected from
the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R.sup.12 is independently selected from selected from the group
consisting of H, halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2,
and --S(O).sub.pR.sup.11, and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy,
arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl,
heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl,
heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy,
heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which
in turn is optionally substituted by at least once by a substituent
selected from the group consisting of H, alkyl, haloalkyl, halo,
--OH, optionally substituted alkoxy, optionally substituted
aryloxy, optionally substituted cycloalkoxy, optionally substituted
heteroaryloxy, optionally substituted heterocyclenyloxy, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11, wherein
said optionally substituted alkoxy, aryloxy, optionally substituted
cycloalkoxy, optionally substituted heteroaryloxy, and
heterocyclenyloxy when substituted are substituted one or more
times by R.sup.11; m is 1 or 2; n is independently 1 or 2; p is
independently 0-2; q is independently 0-3; and w is 1-3, or a
pharmaceutically acceptable salt or solvate thereof.
3. The compound of claim 2, wherein A is imidazole.
4. The compound of claim 1, wherein J.sup.4 is N.
5. The compound of claim 1, wherein J.sup.5 is --N(R.sup.6).
6. The compound of claim 3, wherein J.sup.1 and J.sup.2 are --CH--,
J.sup.3 is --CH-- or --N--, J.sup.4 is N, J.sup.5 is --CH.sub.2--,
m is 1.
7. The compound of claim 6, wherein R.sup.1 is
--(CH).sub.qN(R.sup.7)Y(R.sup.7'); Y is --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.c)--O--, or --C(O)NR.sup.7; R.sup.7 is
independently selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and
heteroarylalkyl, said groups being optionally substituted one or
more times by a substituent independently selected from the group
consisting of H, alkyl, cycloalkyl, alkoxy, halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, --S(O).sub.pR.sup.11, optionally
substituted aryl, optionally substituted aryloxy and optionally
substituted heteroaryloxy, said optionally substituted optionally
substituted aryl, optionally substituted aryloxy and optionally
substituted heteroaryloxy when substituted are independently
substituted one or more times by a substituent selected from the
group consisting of H, alkyl, cycloalkyl, alkoxy, halo, --OH,
NO.sub.2, --N(R.sup.11).sub.2 and --S(O).sub.pR.sup.11.
8. The compound of claim 6, wherein R.sup.1 is
--(CH).sub.qN(R.sup.7)Y(R.sup.7); Y is
--C(.dbd.O)--[C(R.sup.a)(R.sup.b)].sub.n--O--C(.dbd.O)--; R.sup.a
and R.sup.b are independently H or alkyl; n is 1 or 2; and R.sup.7
is independently selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and
heteroarylalkyl, said groups being optionally substituted one or
more times by a substituent independently selected from the group
consisting of H, alkyl, cycloalkyl, alkoxy, halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, --S(O).sub.pR.sup.11, optionally
substituted aryl, optionally substituted aryloxy and optionally
substituted heteroaryloxy, said optionally substituted optionally
substituted aryl, optionally substituted aryloxy and optionally
substituted heteroaryloxy when substituted are independently
substituted one or more times by a substituent selected from the
group consisting of H, alkyl, cycloalkyl, alkoxy, halo, --OH,
NO.sub.2, --N(R.sup.11).sub.2 and --S(O).sub.pR.sup.11.
9. The compound of claim 6, wherein: R.sup.2 is H, halo, or alkyl
groups optionally substituted with at least one R.sup.5; R.sup.3 is
H; R.sup.4 is H, alkyl or CN R.sup.5 is H or halo
10. The compound of claim 9, wherein: R.sup.6 is selected from the
group consisting of H, alkyl and --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.7, --C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7
and --SO.sub.2NR.sup.7R.sup.7';
11. A compound selected from the group consisting of: ##STR413##
##STR414## or a pharmaceutically acceptable salt, ester, solvate,
or prodrug thereof.
12. A pharmaceutical composition comprising at least one compound
of claim 1, or a pharmaceutically acceptable salt or solvate
thereof and at least one pharmaceutically acceptable carrier,
adjuvant or vehicle.
13. The pharmaceutical composition of claim 12, further comprising
one or more additional therapeutic agents.
14. The pharmaceutical composition of claim 13, wherein said
additional therapeutic agents are selected from the group
consisting of steroids, PDE4 inhibitors, anti-muscarinic agents,
cromolyn sodium, H.sub.1 receptor antagonists, 5-HT.sub.1 agonists,
NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin II
receptor agonists, .beta.-blockers, .beta.-agonists, leukotriene
antagonists, diuretics, aldosterone antagonists, ionotropic agents,
natriuretic peptides, pain management agents, anti-anxiety agents,
anti-migraine agents, and therapeutic agents suitable for treating
heart conditions, psychotic disorders, and glaucoma.
15. A method for selectively stimulating .alpha.2C adrenergic
receptors in a cell in need thereof, comprising contacting said
cell with a therapeutically effective amount of at least one
compound of claim 1 or a pharmaceutically acceptable salt or
solvate thereof.
16. A method for treating one or more conditions associated with
.alpha.2C adrenergic receptors, comprising administering to a
mammal in need of such treatment a compound of claim 1 or a
pharmaceutically acceptable salt or solvate thereof.
17. The method of claim 16, wherein the conditions are selected
from the group consisting of allergic rhinitis, congestion, pain,
diarrhea, glaucoma, congestive heart failure, cardiac ischemia,
manic disorders, depression, anxiety, migraine, stress-induced
urinary incontinence, neuronal damage from ischemia and
schizophrenia.
18. The method of claim 17, wherein the condition is
congestion.
19. The method of claim 18, wherein the congestion is associated
with perennial allergic rhinitis, seasonal allergic rhinitis,
non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa,
sinusitis, acute rhinosinusitis, or chronic rhinosinusitis.
20. The method of claim 18, wherein the congestion is caused by
polyps or is associated with the common cold.
21. The method of claim 16, wherein the condition is pain.
22. The method of claim 21, wherein the pain is associated with
neuropathy, inflammation, arthritis, diabetes.
23. A compound of claim 1, in isolated and purified form.
24. A pharmaceutical composition comprising at least one compound
of claim 11, or a pharmaceutically acceptable salt or solvate
thereof and at least one pharmaceutically acceptable carrier,
adjuvant or vehicle.
25. The pharmaceutical composition of claim 24, further comprising
one or more additional therapeutic agents.
26. The pharmaceutical composition of claim 25, wherein said
additional therapeutic agents are selected from the group
consisting of steroids, PDE-4 inhibitors, anti-muscarinic agents,
cromolyn sodium, H.sub.1 receptor antagonists, 5-HT.sub.1 agonists,
NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin II
receptor agonists, .beta.-blockers, .beta.-agonists, leukotriene
antagonists, diuretics, aldosterone antagonists, ionotropic agents,
natriuretic peptides, pain management agents, anti-anxiety agents,
anti-migraine agents, and therapeutic agents suitable for treating
heart conditions, psychotic disorders, and glaucoma.
27. A method for treating one or more conditions associated with
.alpha.2C adrenergic receptors, comprising administering to a
mammal in need of such treatment a compound of claim 11 or a
pharmaceutically acceptable salt or solvate thereof.
28. The method of claim 27, wherein the conditions are selected
from the group consisting of allergic rhinitis, congestion, pain,
diarrhea, glaucoma, congestive heart failure, cardiac ischemia,
manic disorders, depression, anxiety, migraine, stress-induced
urinary incontinence, neuronal damage from ischemia and
schizophrenia.
29. The method of claim 28, wherein the condition is
congestion.
30. The method of claim 29, wherein the congestion is associated
with perennial allergic rhinitis, seasonal allergic rhinitis,
non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa,
sinusitis, acute rhinosinusitis, or chronic rhinosinusitis.
31. The method of claim 29, wherein the congestion is caused by
polyps or is associated with the common cold.
32. The method of claim 28, wherein the condition is pain.
34. The method of claim 32 wherein the pain is associated with
neuropathy, inflammation, arthritis, diabetes.
35. A compound of claim 11, in isolated and purified form.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part to application
U.S. Ser. No. 11/508,458, filed Aug. 23, 2006, herein incorporated
by reference, which in turn claims priority to provisional
application U.S. Ser. No. 60/711,398, filed on Aug. 25, 2005,
herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to indoline compounds useful
as .alpha.2C adrenergic receptor agonists, methods for making the
compounds, pharmaceutical compositions containing the compounds,
and methods of treatment and prevention using the compounds and
compositions to treat disease states such as congestion (including
nasal), migraine, congestive heart failure, cardiac ischemia,
glaucoma, pain and psychotic disorders without substantial adverse
side effects associated with .alpha.2A receptor agonist
treatments.
BACKGROUND OF THE INVENTION
[0003] The initial classification of adrenergic receptors into
.alpha.- and .beta.-families was first described by Ahlquist in
1948 (Ahlquist RP, "A Study of the Adrenergic Receptors," Am. J.
Physiol. 153:586-600 (1948)). Functionally, the .alpha.-adrenergic
receptors were shown to be associated with most of the excitatory
functions (vasoconstriction, stimulation of the uterus and pupil
dilation). .beta.-adrenergic receptors were implicated in
vasodilation, bronchodilation and myocardial stimulation (Lands et
al., "Differentiation of Receptor Systems Activated by
Sympathomimetic amines," Nature 214:597-598 (1967)). Since this
early work, .alpha.-adrenergic receptors have been subdivided into
.alpha.1- and .alpha.2-adrenergic receptors. Cloning and expression
of .alpha.-adrenergic receptors have confirmed the presence of
multiple subtypes of both .alpha.1-(.alpha.1A, .alpha.1B,
.alpha.1D) and .alpha.2-(.alpha.2A, .alpha.2B, .alpha.2C)
adrenergic receptors (Michel et al., "Classification of
.alpha..sub.1-Adrenoceptor Subtypes," Naunyn-Schmiedeberg's Arch.
Pharmacol, 352:1-10 (1995); Macdonald et al., "Gene
Targeting--Homing in on .alpha..sub.2-Adrenoceptor-Subtype
Function," TIPS, 18:211-219 (1997)).
[0004] Current therapeutic uses of .alpha.-2 adrenergic receptor
drugs involve the ability of those drugs to mediate many of the
physiological actions of the endogenous catecholamines. There are
many drugs that act on these receptors to control hypertension,
intraocular pressure, eye reddening and nasal congestion and induce
analgesia and anesthesia.
[0005] .alpha.2 adrenergic receptors can be found in the rostral
ventrolateral medulla, and are known to respond to the
neurotransmitter norepinephrine and the antihypertensive drug
clonidine to decrease sympathetic outflow and reduce arterial blood
pressure (Bousquet et al., "Role of the Ventral Surface of the
Brain Stem in the Hypothesive Action of Clonidine," Eur. J.
Pharmacol., 34:151-156 (1975); Bousquet et al., "Imidazoline
Receptors: From Basic Concepts to Recent Developments," 26:S1-S6
(1995)). Clonidine and other imidazolines also bind to imidazoline
receptors (formerly called imidazoline-guanidinium receptive sites
or IGRS) (Bousquet et al., "Imidazoline Receptors: From Basic
Concepts to Recent Developments," 26:S1-S6 (1995)). Some
researchers have speculated that the central and peripheral effects
of imidazolines as hypotensive agents may be related to imidazoline
receptors (Bousquet et al., "Imidazoline Receptors: From Basic
Concepts to Recent Developments," 26:S1-S6 (1995); Reis et al.,
"The Imidazoline Receptor: Pharmacology, Functions, Ligands, and
Relevance to Biology and Medicine," Ann. N.Y. Acad. Sci., 763:1-703
(1995).
[0006] Compounds having adrenergic activity are well-known in the
art, and are described in numerous patents and scientific
publications It is generally known that adrenergic activity is
useful for treating animals of the mammalian species, including
humans, for curing or alleviating the symptoms and conditions of
numerous diseases and conditions. In other words, it is generally
accepted in the art that pharmaceutical compositions having an
adrenergic compound or compounds as the active ingredient are
useful for treating, among other things, glaucoma, chronic pain,
migraines, heart failure, and psychotic disorders.
[0007] For example, published PCT application WO 02/076950
discloses compounds having .alpha.2 agonist activity of the
following general formula: ##STR1##
[0008] Another class of compounds having .alpha.2-agonist
properties is disclosed in U.S. Pat. No. 5,658,938, and has the
following general formula: ##STR2## wherein n=1-2, R.sup.1-R.sup.3
represent hydrogen, halogen hydroxy, alkyl or alkoxy, and R.sup.5
is hydrogen or alkyl.
[0009] Another class of compounds reported to have affinity for
.alpha.2 receptors includes the following two compounds (Bagley et.
al., Med. Chem. Res. 1994, 4:346-364): ##STR3##
[0010] Another class of compounds reported to have affinity for
.alpha.2 receptors includes the following two compounds (Miller et.
al., J. Med. Chem. 1994, 37:2328-2333; J. Med. Chem. 1996,
39:3001-3013; J. Med. Chem. 1997, 37:3014-3024): ##STR4## Another
class of indane and tetrahyrdonaphthalene type compounds having
.alpha.2-agonist properties is disclosed in PCT application WO
97/12874 and WO20040506356 This class has the following general
formula: ##STR5## wherein n=0-1, X is 1 or 2 carbon units, R.sup.4
is H, OH, alkyl, or alkoxy, R.sub.5 may be taken together with
R.sup.4 to form a carbonyl, and R.sup.6-R.sup.8.dbd.H, OH, SH,
alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, alkylthio,
alkylthiol, halo, CF.sub.3, NO.sub.2, or alkylamino. This class
specifically includes MPV-2426 (fadolmidine) and its prodrug
esters: ##STR6## wherein R is optionally substituted lower alkyl,
aryl, cycloalkyl, heteroaryl, lower alkylamino, and saturated. 5-
or 6-membered heterocyclic groups containing. 1 or 2 N atoms
[0011] It is also known that compounds having adrenergic activity,
such as .alpha.2A agonists, may be associated with undesirable side
effects. Examples of such side effects include hyper- and
hypotension, sedation, locomotor activity, and body temperature
variations.
[0012] It has been discovered in accordance with the present
invention that adrenergic compounds that act selectively, and
preferably even specifically, as agonists of the .alpha.2C or the
.alpha.2B/.alpha.2C (hereinafter referred to as .alpha.2C or
.alpha.2B/2C) receptor subtypes in preference over the .alpha.2A
receptor subtype, with the adrenergic compounds that are
functionally selective agonists of the .alpha.2C or the
.alpha.2B/2C receptor subtype in preference over the .alpha.2A
receptor subtype, possess desirable therapeutic properties
associated with adrenergic receptors but without having one or more
undesirable side effects such as changes in blood pressure or
sedation. For the purposes of the present invention, a compound is
defined to be a specific or at least functionally selective agonist
of the .alpha.2C receptor subtype over the .alpha.2A receptor
subtype if the compound's efficacy at the .alpha.2C receptor is
.gtoreq.30% E.sub.max (GTP.gamma.S assay) and its efficacy at the
.alpha.2A receptor is .ltoreq.30% E.sub.max (GTP.gamma.S
assay).
[0013] There is a need for new compounds, formulations, treatments
and therapies to treat diseases and disorders associated with
.alpha.2C adrenergic receptors while minimizing adverse side
effects. Further, there is a need to develop compounds that are
functionally selective for the .alpha.2C or the .alpha.2B/2C
receptor subtype with respect to the .alpha.2A receptor subtype. It
is, therefore, an object of this invention to provide compounds
useful in the treatment or prevention or amelioration of such
diseases and disorders.
SUMMARY OF THE INVENTION
[0014] In its many embodiments, the present invention provides a
novel class of heterocyclic compounds as functionally selective
.alpha.2C adrenergic receptor agonists, or metabolites,
stereoisomers, salts, solvates or polymorphs thereof, methods of
preparing such compounds, pharmaceutical compositions comprising
one or more such compounds, methods of preparing pharmaceutical
formulations comprising one or more such compounds, and methods of
treatment, prevention, inhibition or amelioration of one or more
conditions associated with .alpha.2C receptors using such compounds
or pharmaceutical compositions.
[0015] In one aspect, the present application discloses a compound,
or pharmaceutically acceptable salts or metabolites, solvates,
polymorphs or prodrugs of said compound, said compound having the
general structure shown in Formula I: ##STR7## wherein:
[0016] A is a 5-membered heterocyclic ring containing 1-3
heteroatoms, and is optionally substituted with at least one
R.sup.5 and/or 1 or 2 (.dbd.O) (carbonyl) groups;
[0017] J.sup.1, J.sup.2, and J.sup.3 are independently --N--,
--N(O)-- or --C(R.sup.2)--;
[0018] J.sup.4 is C or N;
[0019] J.sup.5 is --C(R.sup.6)-- or --N(R.sup.6)--;
[0020] is a single or double bond;
[0021] R.sup.1 is selected from the group consisting of
--[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qN(R.sup.7)YR.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qNR.sup.7R.sup.7'',
[C(R.sup.a)(R.sup.b)].sub.qOYR.sup.7',
--[C(R.sup.a)(R.sup.b)].sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, and
--P(.dbd.O)R.sup.8.sub.2;
[0022] Y is selected from the group consisting of a bond,
--C(.dbd.O)--, --C(.dbd.O)NR.sup.7, --C(.dbd.O)O--,
--C(.dbd.O)-[C(R.sup.a)(R.sup.b).sub.n--O--C(.dbd.O)--,
--C(.dbd.O)N(R.sup.c)--O--, --C(.dbd.NR.sup.7)--,
--C(.dbd.NOR.sup.7)--, --C(.dbd.NR.sup.7)NR.sup.7--,
--C(.dbd.NR.sup.7)NR.sup.7O--, --S(O).sub.p--,
--SO.sub.2NR.sup.7--, and --C(.dbd.S)NR.sup.7--; [0023] wherein
R.sup.a and R.sup.b are independently selected from the group
consisting of H, alkyl, alkoxy, and halo, and [0024] R.sup.cC is H
or alkyl;
[0025] R.sup.2 is independently selected from the group consisting
of H, --OH, halo, --CN, --NO.sub.2, --S(O).sub.pR.sup.7,
--NR.sup.7R.sup.7', --(CH.sub.2).sub.qYR.sup.7',
--(CH.sub.2).sub.qN(R.sup.7)YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7',
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7')(OR.sup.7'), --P(.dbd.O)NR.sup.7R.sup.7', and
--P(.dbd.O)R.sup.8.sub.2, and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5;
[0026] R.sup.3 is independently selected from the group consisting
of H, halo and (.dbd.O), and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5, provided
that when w is 3, no more than 2 of the R.sup.3 groups may be
(.dbd.O);
[0027] R.sup.4 is independently selected from the group consisting
of H, --CN and halo, and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5;
[0028] R.sup.5 is independently selected from the group consisting
of H, halo, --OH, --CN, --NO.sub.2, --NR.sup.7R.sup.7', and
--S(O).sub.pR.sup.7, and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --NR.sup.7R.sup.7', and
--S(O).sub.pR.sup.7 substituents and/or 1 or 2 (.dbd.O) groups;
[0029] R.sup.6 is independently selected from the group consisting
of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents and/or 1 or 2 (.dbd.O) groups, and --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.7, --C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7
and --SO.sub.2NR.sup.7R.sup.7';
[0030] R.sup.7 is independently selected from the group consisting
of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cyclocyclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heterocyclenyl, heterocyclenylalkyl, heteroaryl,
and heteroarylalkyl, each of which is optionally substituted one or
more times (preferably 1 to 5, more preferably 1 to 3) by
R.sup.12;
[0031] R.sup.7' is independently selected from the group consisting
of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cyclocyclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heterocyclenyl, heterocyclenylalkyl, heteroaryl,
and heteroarylalkyl, each of which is optionally substituted one or
more times (preferably 1 to 5, more preferably 1 to 3) by R.sup.12;
[0032] R.sup.7 and R.sup.7' together with the nitrogen atom to
which they are attached form a 3- to 8-membered heterocyclyl,
heterocyclenyl or heteroaryl ring having, in addition to the N
atom, 1 or 2 additional hetero atoms selected from the group
consisting of O, N, --N(R.sup.9)-- and S, wherein said rings are
optionally substituted by 1 to 5 independently selected R.sup.5
moieties and/or 1 or 2 (.dbd.O) groups,
[0033] R.sup.8 is independently selected from the group consisting
of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heterocyclyl, heteroaryl, and heteroarylalkyl groups, each of which
is optionally substituted with at least one of halo, alkoxy, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11
substituents and/or 1 or 2 (.dbd.O) groups;
[0034] R.sup.9 is independently selected from the group consisting
of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11
substituents and/or 1 or 2 (.dbd.O) groups; and
[0035] R.sup.10 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11 substituents and/or 1
or 2 (.dbd.O) groups;
[0036] R.sup.11 is a moiety independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which
is optionally substituted by at least one substituent independently
selected from the group consisting of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11').sub.2, and --S(O).sub.pR.sup.11' and/or 1 or 2
(.dbd.O) groups;
[0037] R.sup.11' is independently selected from the group
consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[0038] R.sup.12 is independently selected from selected from the
group consisting of H, halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11 and/or 1 or 2
(.dbd.O) groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl,
heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl,
heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy,
heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which
in turn is optionally substituted by at least once (preferably 1 to
5, more preferably 1 to 3) by a substituent selected from the group
consisting of H, alkyl, haloalkyl, halo, --OH, optionally
substituted alkoxy, optionally substituted aryloxy, optionally
substituted cycloalkoxy, optionally substituted heteroaryloxy,
optionally substituted heterocyclenyloxy, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11 and/or 1 or 2
(.dbd.O) groups, wherein said optionally substituted alkoxy,
aryloxy, optionally substituted cycloalkoxy, optionally substituted
heteroaryloxy, and heterocyclenyloxy when substituted are
substituted one or more (preferably 1 to 5, more preferably 1 to 3)
times by R.sup.11;
[0039] m is 1-5;
[0040] n is independently 1-3;
[0041] p is independently 0-2;
[0042] q is independently 0-6; and
[0043] w is 1-3;
[0044] with the following provisos:
[0045] (a) if J.sup.1-J.sup.3 are --C(H)--, R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qOYR.sup.7', q is 0, and A is
unsubstituted imidazolyl, then Y is other than a bond;
[0046] (b) if J.sup.1-J.sup.3 are --C(H)--, R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7', q is 0, and A is
unsubstituted imidazolyl, then Y is other than a bond;
[0047] (c) if J.sup.4 is N, then J.sup.5 is --C(R.sup.6)--;
[0048] (d) if J.sup.4 is C, then J.sup.5 is --N(R.sup.6)-- and
[0049] (e) if A is unsubstituted imidazolyl, R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7', q is 0, Y is --C(.dbd.O)--
or --C(.dbd.O)O--, then R.sup.7 is other than H or alkyl
[0050] (f) if R.sup.1 is --[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7',
q=0, and Y=--C(.dbd.NR.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, or --C(.dbd.NR.sup.7)N(R.sup.c)O--,
then R.sup.7 and R.sup.7' may not be taken together to form a 3- to
8-membered heterocyclyl, heterocyclenyl or heteroaryl ring; and
[0051] (g) if R.sup.1 is
--[C(R.sup.a)(R.sup.b)].sub.qN(R.sup.7)YR.sup.7' or
--[C(R.sup.a)(R.sup.b)].sub.qNR.sup.7R.sup.7' and q=0, then R.sup.7
and R.sup.7' may not be taken together to form a 3- to 8-membered
heterocyclyl, heterocyclenyl or heteroaryl ring.
[0052] The compounds of Formula I can be useful as .alpha.2C
adrenergic receptor agonists, and can be useful in the treatment
and prevention of allergic rhinitis, congestion (including, but not
limited to nasal congestion), migraine, congestive heart failure,
cardiac ischemia, glaucoma, stress-induced urinary incontinence,
neuronal damage from ischemia and psychotic disorders. Further, the
compounds of Formula I can be useful in the treatment of pain (both
chronic and acute), such as pain that is caused by inflammation,
neuropathy, arthritis (including osteo and rheumatoid arthritis),
diabetes (e.g., diabetes mellitus or diabetes insipidus) or pain of
an unknown origin. Examples of neuropathic pain may include but not
limited to; diabetic neuropathy, neuralgia of any etiology (e.g.
post-herpetic, trigeminal), chemotherapy-induced neuropathy, HIV,
lower back pain of neuropathic origin (e.g. sciatica), traumatic
peripheral nerve injury of any etiology, central pain (e.g.
post-stroke, thalamic, spinal nerve injury). Other pain that can be
treated is nociceptive pain and pain that is visceral in origin or
pain that is secondary to inflammation or nerve damage in other
diseases or diseases of unknown origin.
[0053] Alternatively, the present invention provides for a method
for the treatment of congestion in a mammal in need thereof which
comprises administering to a mammal an effective dose of at least
one compound having adrenergic activity wherein said compound is a
functionally selective agonist of the .alpha.2c receptor.
[0054] A further embodiment of the present invention is a method
for the treatment of congestion in a mammal in need thereof which
comprises administering to a mammal an effective dose of at least
one compound having adrenergic activity wherein said compound is a
functionally selective agonist of the .alpha.2C receptor, wherein
the selective agonist of the .alpha.2c receptor has an efficacy
that is greater than or equal to 30% E.sub.max when assayed in the
GTP.gamma.S assay and its efficacy at the .alpha.2A receptor is
.ltoreq.30% E.sub.max (GTP.gamma.S assay).
[0055] Another embodiment of the present invention is a method for
the treatment of congestion in a mammal in need thereof without
modifying the blood pressure at therapeutic doses which comprises
administering to the mammal an effective dose of at least one
compound having adrenergic activity wherein said compound is a
selective agonist of the .alpha.2C receptor.
DETAILED DESCRIPTION
[0056] In an embodiment, the present invention discloses certain
heterocyclic compounds which are represented by structural Formula
I, or a pharmaceutically acceptable salt or solvate thereof,
wherein the various moieties are as described above.
[0057] In one embodiment, if J.sup.1-J.sup.3 are --C(H)--, R.sup.1
is --[C(R.sup.a)(R.sup.b)].sub.qOYR.sup.7', q is 0, and A is
unsubstituted imidazolyl, then Y is other than a bond.
[0058] In another embodiment, if J.sup.1-J.sup.3 are --C(H)--,
R.sup.a is --[C(R.sup.a)(R.sup.b)].sub.qYR.sup.7', q is 0, and A is
unsubstituted imidazolyl, then Y is other than a bond.
[0059] In another embodiment, J.sup.1 is --N--.
[0060] In another embodiment, J.sup.2 is --N--.
[0061] In another embodiment, J.sup.3 is --N--.
[0062] In another embodiment, J.sup.2 and J.sup.3 are both
--N--.
[0063] In another embodiment, if J.sup.4 is N, then J.sup.5 is
--C(R.sup.6)--.
[0064] In another embodiment, if J.sup.4 is C, then J.sup.5 is
--N(R.sup.6)--.
[0065] In another embodiment, J.sup.1-J.sup.3 are each
--C(R.sup.2)--, preferably --CH--.
In another embodiment, A is a 5-membered heterocyclic ring
containing at least one ring nitrogen.
[0066] In another embodiment, A is a 5-membered heteroaryl,
heterocyclyl or heterocyclenyl ring containing at least one ring
nitrogen.
[0067] In another embodiment A is an optionally substituted
5-membered heteroaryl, heterocyclenyl or heterocyclyl ring.
Preferred optionally substituted heteroaryl, heterocyclenyl or
heterocyclyl 5-membered rings include, for example, imidazole,
thiazole, pyrrole, isoxazole, oxazole, isothiazole, pyrazole,
imadazoline, imidazol-2-one, imidazol-2-thione, 2-aminoimidazoline,
oxazoline, oxazol-2-one, oxazol-2-thione, 2-aminooxazoline,
thiazoline, thiazol-2-one, thiazol-2-thione, 2-aminothiazoline,
pyrroline, pyrazoline, pyrrolidine, imidazolidine, and
pyrazolidine. A more preferred set of 5-membered rings includes:
imidazole, imadazoline, imidazol-2-one, imidazol-2-thione,
2-aminoimidazoline, oxazoline, oxazol-2-one, oxazol-2-thione, and
2-aminooxazoline. A most preferred set of 5-membered rings includes
imidazole. Optionally substituents include any of the "ring system
substituents" identified below.
[0068] In another embodiment, R.sup.1 is selected from
--(CH.sub.2).sub.qYR.sup.7', --(CH.sub.2).sub.qNR.sup.7YR.sup.7',
--(CH.sub.2).sub.qN(R.sup.7)R.sup.7', --(CH.sub.2).sub.qOYR.sup.7',
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'), P(.dbd.O)(NR.sup.7R.sup.7'), and
--P(.dbd.O)R.sup.8.sub.2.
[0069] In another embodiment, Y is selected from a bond,
--C(.dbd.O)--, --C(.dbd.O)NR.sup.7--, --C(.dbd.O)O--,
--C(.dbd.NR.sup.7)--,
--C(.dbd.O)--[C(R.sup.a)(R.sup.b)].sub.n--O--C(.dbd.O)--,
C(.dbd.O)N(R.sup.c)--O--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, --SO.sub.2NR.sup.7--, and
--C(.dbd.S)NR.sup.7--.
[0070] In another embodiment, R.sup.1 is
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', q=0, Y is --C(.dbd.O)--,
--C(.dbd.O)NR.sup.7--or --C(.dbd.O)O--, and R.sup.7 is Me or
Et.
[0071] In another embodiment, R.sup.2 is independently selected
from the group consisting of H, --OH, halo, --CN, --NO.sub.2,
--SR.sup.7, --NR.sup.7R.sup.7', --(CH.sub.2).sub.qYR.sup.7',
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', (CH.sub.2).sub.qOYR.sup.7',
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'), --P(.dbd.O)NR.sup.7R.sup.7', and
--P(.dbd.O)R.sup.8.sub.2, and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5.
[0072] In another embodiment, R.sup.3 is independently selected
from H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5.
[0073] In another embodiment, R.sup.4 is independently selected
from H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5.
[0074] In another embodiment, R.sup.4 is independently selected
from H and alkyl.
[0075] In another embodiment, R.sup.5 is independently selected
from H, halo, --OH, --CN, --NO.sub.2, --NR.sup.7R.sup.7', and
--SR.sup.7, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each
of which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents.
[0076] In another embodiment, R.sup.6 is independently selected
from H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2--NR.sup.7R.sup.7'.
[0077] In another embodiment, R.sup.7 is independently selected
from the group consisting of H and alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, cyclocyclenyl, cyclocyclenylalkyl,
aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclenyl,
heterocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each
of which is optionally substituted one or more times (preferably 1
to 5, more preferably 1 to 3) by R.sup.12.
[0078] In another embodiment, R.sup.7' is independently selected
from the group consisting of H and alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, cyclocyclenyl, cyclocyclenylalkyl,
aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclenyl,
heterocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each
of which is optionally substituted one or more times (preferably 1
to 5, more preferably 1 to 3) by R.sup.12.
[0079] In another embodiment, R.sup.7 and R.sup.7' together with
the N atom to which they are attached form a aziridine, azetidine,
pyrrole, pyrrolidine, piperidine, piperazine or morpholine ring,
each of which are optionally substituted by R.sup.5.
[0080] In another embodiment, R.sup.8 is independently selected
from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heterocyclyl, heteroaryl, and heteroarylalkyl groups, each of which
is optionally substituted with at least one of halo, alkoxy, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents.
[0081] In another embodiment R.sup.12 is independently an
arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and
heterocyclenylalkoxy group, each of which in turn is optionally
substituted by at least once (preferably 1 to 5, more preferably 1
to 3) by a substituent selected from the group consisting of H,
alkyl, haloalkyl, halo, --OH, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted cycloalkoxy,
optionally substituted heteroaryloxy, optionally substituted
heterocyclenyloxy, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--S(O).sub.pR.sup.11, wherein said optionally substituted alkoxy,
aryloxy, optionally substituted cycloalkoxy, optionally substituted
heteroaryloxy, and heterocyclenyloxy when substituted are
substituted one or more (preferably 1 to 5, more preferably 1 to 3)
times by R.sup.11.
[0082] In another embodiment R.sup.12 is independently selected
from the group consisting of H, halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11, and alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy,
heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy,
heterocyclylalkyl, heterocyclenylalkyl, groups, each of which in
turn is optionally substituted by at least once (preferably 1 to 5,
more preferably 1 to 3) by a substituent selected from the group
consisting of H, alkyl, haloalkyl, halo, --OH, optionally
substituted alkoxy, optionally substituted aryloxy, optionally
substituted cycloalkoxy, optionally substituted heteroaryloxy,
optionally substituted heterocyclenyloxy, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --S(O).sub.pR.sup.11, wherein said
optionally substituted alkoxy, aryloxy, optionally substituted
cycloalkoxy, optionally substituted heteroaryloxy, and
heterocyclenyloxy when substituted are substituted one or more
(preferably 1 to 5, more preferably 1 to 3) times by R.sup.11.
[0083] In another embodiment, m is 1.
[0084] In another embodiment, n is 1.
[0085] In another embodiment, n is 2.
[0086] In another embodiment, p is 0-2.
[0087] In another embodiment, q is 0-3.
[0088] In another embodiment, A is imidazolyl.
[0089] In another embodiment, J.sup.4 is N.
[0090] In another embodiment, J.sup.5 is --N(R.sup.6)--.
[0091] In another embodiment. A is imidazole, J.sup.1, J.sup.2 and
J.sup.3 are --CH--, J.sup.4 is N, J.sup.5 is --CH.sub.2-- or
--CH(R.sub.2)--, m is 1.
[0092] In another embodiment R.sup.1 is
--(CH.sub.2).sub.qYR.sup.7', or
--(CH.sub.2).sub.qN(R.sup.7)YR.sup.7', Y is
--C(.dbd.O)--[C(R.sup.a)(R.sup.b)].sub.n--O--C(.dbd.O)--, n is 1 or
2, and R.sup.a and R.sup.b are independently H or alkyl (preferably
methyl or ethyl).
[0093] In another embodiment, A is optionally substituted
imidazole,
[0094] R.sup.1 is --(CH).sub.qN(R.sup.7)Y(R.sup.7');
[0095] Y is --C(.dbd.O)O--, --C(.dbd.O)N(R.sup.c)--O--, or
--C(O)NR.sup.7; and
[0096] R.sup.7 is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
arylalkyl, and heteroarylalkyl, said groups being optionally
substituted one or more times by a substituent independently
selected from the group consisting of H, alkyl, cycloalkyl, alkoxy,
halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2,
--S(O).sub.pR.sup.11, optionally substituted aryl, optionally
substituted aryloxy and optionally substituted heteroaryloxy, said
optionally substituted optionally substituted aryl, optionally
substituted aryloxy and optionally substituted heteroaryloxy when
substituted are independently substituted one or more times by a
substituent selected from the group consisting of H, alkyl,
cycloalkyl, alkoxy, halo, --OH, NO.sub.2, --N(R.sup.11).sub.2 and
--S(O).sub.pR.sup.11.
[0097] In another embodiment, the present invention discloses
compounds which are represented by structural formulae II-V or a
pharmaceutically acceptable salt, solvate or ester thereof, wherein
the various moieties are as described above: ##STR8## wherein X is
halo or H and z is 0-3.
[0098] An inventive group of compounds is shown below: ##STR9##
##STR10## ##STR11## ##STR12## ##STR13## ##STR14## ##STR15##
##STR16##
[0099] Another group of inventive compounds includes the following:
##STR17## ##STR18## or a pharmaceutically acceptable salt, ester,
solvate, or prodrug thereof.
[0100] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0101] "Patient" includes both human and animals.
[0102] "Mammal" means humans and other mammalian animals.
[0103] "Congestion" refers to all type of congestion including, but
not limited to, congestion associated with perennial allergic
rhinitis, seasonal allergic rhinitis, non-allergic rhinitis,
vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute
rhinosinusitis, or chronic rhinosinusitis or when the congestion is
caused by polyps or is associated with the common cold.
[0104] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0105] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means
that the alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0106] "Aryl" means an aromatic monocyclic or multicyclic ring
system, in which at least one of the multicyclic rings is an aryl
ring, comprising about 6 to about 14 carbon atoms, preferably about
6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
Non-limiting examples of aryl multicyclic ring systems include:
##STR19##
[0107] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system, in which at least one of the multicyclic rings is
aromatic, comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. Non-limiting examples of suitable
heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,
pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,
benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,
quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,
benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.
[0108] Non-limiting examples of hetreroaryl multicyclic ring
systems include: ##STR20##
[0109] "Aralkyl" or "arylalkyl" means an aryl-alkyl-group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0110] "Alkylaryl" means an alkyl-aryl- group in which the alkyl
and aryl are as previously described. Preferred alkylaryls comprise
a lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0111] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like.
[0112] "Halogen" and "Halo" mean fluorine, chlorine, bromine, or
iodine. Preferred are fluorine, chlorine or bromine, and more
preferred are fluorine and chlorine.
[0113] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl,
heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)-- and Y.sub.1Y.sub.2NSO.sub.2--, wherein
Y.sub.1 and Y.sub.2 may be the same or different and are
independently selected from the group consisting of hydrogen,
alkyl, aryl, and aralkyl.
[0114] "Heterocyclyl" means a non-aromatic saturated monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 5 to about 10 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur, alone or in combination. There
are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocyclyls contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Any --NH in a heterocyclyl
ring may exist protected such as, for example, as an --N(Boc),
--N(CBz), --N(Tos) group and the like; such protected moieties are
also considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, and the like.
[0115] Compounds of Formula I and salts, esters, solvates and
prodrugs thereof, may exist in their tautomeric form (for example,
as an amide or imino ether). All such tautomeric forms are
contemplated herein as part of the present invention. Non-limiting
examples of tautomeric forms that are part of this invention are as
follows: ##STR21##
[0116] It should be noted that in saturated heterocyclyl containing
systems of this invention, there are no hydroxyl, amino, or thiol
groups on carbon atoms adjacent to a N, O or S atom. Thus, for
example, in the ring: ##STR22## there is no --OH attached directly
to carbons marked 2 and 5. It should also be noted that this
definition does not preclude (.dbd.O), (.dbd.S), or (.dbd.N)
substitutions, or their tautomeric forms, on C atoms adjacent to a
N, O or S. Thus, for example, in the above ring, (.dbd.O)
substitution on carbon 5, or its imino ether tautomer is
allowed.
[0117] Non-limiting examples which illustrate the present invention
are as follows: ##STR23## The following non-limiting examples serve
to illustrate radicals not contemplated by the present invention:
##STR24##
[0118] "Alkynylalkyl" means an alkynyl-alkyl- group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group. The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0119] "Heteroaralkyl" or "heteroarylalkyl" means a
heteroaryl-alkyl- group in which the heteroaryl and alkyl are as
previously described. Preferred heteroaralkyls contain a lower
alkyl group. Non-limiting examples of suitable aralkyl groups
include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the
parent moiety is through the alkyl.
[0120] "Heterocyclylalkyl" means a heterocyclyl-alkyl group in
which the heterocyclyl and the alkyl are as previously described.
Preferred heterocyclylalkyls contain a lower alkyl group.
Non-limiting examples of suitable heterocyclylalkyl groups include
piperidylmethyl, piperidylethyl, pyrrolidylmethyl,
morpholinylpropyl, piperazinylethyl, azindylmethyl, azetidylethyl,
oxiranylpropyl and the like. The bond to the parent moiety is
through the alkyl group.
[0121] "Heterocyclenyl" (or "heterocycloalkeneyl") means a
non-aromatic monocyclic or multicyclic ring system comprising about
3 to about 10 ring atoms, preferably about 5 to about 10 ring
atoms, in which one or more of the atoms in the ring system is an
element other than carbon, for example nitrogen, oxygen or sulfur
atom, alone or in combination, and which contains at least one
carbon-carbon double bond or carbon-nitrogen double bond. There are
no adjacent oxygen and/or sulfur atoms present in the ring system.
Preferred heterocyclenyl rings contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclenyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. The heterocyclenyl can be
optionally substituted by one or more ring system substituents,
wherein "ring system substituent" is as defined above. The nitrogen
or sulfur atom of the heterocyclenyl can be optionally oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting
examples of suitable monocyclic azaheterocyclenyl groups include
1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,
1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl,
2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the
like. Non-limiting examples of suitable oxaheterocyclenyl groups
include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl,
and the like. Non-limiting example of a suitable multicyclic
oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
Non-limiting examples of suitable monocyclic thiaheterocyclenyl
rings include dihydrothiophenyl, dihydrothiopyranyl, and the
like.
[0122] "Heterocyclenylalkyl" means a heterocyclenyl-alkyl group in
which the heterocyclenyl and the alkyl are as previously
described.
[0123] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0124] "Acyl" means an organic acid group in which the --OH of the
carboxyl group is replaced by some other substituent. Suitable
non-limiting examples include H--C(O)--, alkyl-C(O)--,
cycloalkyl-C(O)--, heterocyclyl-C(O)--, and heteroaryl-C(O)--
groups in which the various groups are as previously described. The
bond to the parent moiety is through the carbonyl. Preferred acyls
contain a lower alkyl. Non-limiting examples of suitable acyl
groups include formyl, acetyl and propanoyl.
[0125] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0126] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0127] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0128] "Aralkyloxy" or "arylalkyloxy" means an aralkyl-O-- group in
which the aralkyl group is as previously described. Non-limiting
examples of suitable aralkyloxy groups include benzyloxy and 1- or
2-naphthalenemethoxy. The bond to the parent moiety is through the
ether oxygen.
[0129] "Heteroarylalkoxy" means a heteroarylalkyl-O-group in which
the heteroarylalkyl group is as previously described.
[0130] "Heterocyclylalkoxy" means a heterocyclylalkyl-O group in
which the hetrocyclylalkyl group is as previously described.
[0131] "Heterocyclenylalkoxy" means a heterocyclenylalkyl-O group
in which the heterocyclenylalkyl group is as previously
described.
[0132] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0133] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0134] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0135] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0136] "Aryloxycarbonyl" means an aryl-O--C(O)-- group.
Non-limiting examples of suitable aryloxycarbonyl groups include
phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent
moiety is through the carbonyl.
[0137] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group.
Non-limiting example of a suitable aralkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0138] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group. Preferred
groups are those in which the alkyl group is lower alkyl. The bond
to the parent moiety is through the sulfonyl.
[0139] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group. The bond to
the parent moiety is through the sulfonyl.
[0140] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound" or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0141] It is noted that carbons of formula I can be replaced with
1-3 silicon atoms, provided all valency requirements are
satisfied.
[0142] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[0143] It should also be noted that any heteroatom with unsatisfied
valences in the text, schemes, examples and Tables herein is
assumed to have the hydrogen atom to satisfy the valences.
[0144] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction. Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[0145] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or formula, its
definition on each occurrence is independent of its definition at
every other occurrence.
[0146] Unless defined otherwise, all definitions for the variables
follow the convention that the group to the right forms the point
of attachment to the molecule; i.e., if a definition is arylalkyl,
this means that the alkyl portion of the definition is attached to
the molecule.
[0147] Further, all divalent variable are attached from left to
right. For example when R.sup.1 is
--(CH.sub.2).sub.qN(R.sup.7)YR.sup.7', and Y is
--C(.dbd.O)--[C(R.sup.a)(R.sup.b)].sub.n--O--C(.dbd.O)--, then
R.sup.1 forms the group
--(CH.sub.2).sub.qN(R.sup.7)--C(.dbd.O)--[C(R.sup.a)(R.sup.b)].sub.n--O---
C(.dbd.O)--R.sup.7'.
[0148] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0149] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound that is a drug precursor which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of formula I or
a salt and/or solvate thereof. A discussion of prodrugs is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) Volume 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,
American Pharmaceutical Association and Pergamon Press, both of
which are incorporated herein by reference thereto.
[0150] For example, if a compound of Formula (I) or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as, for example,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.12)alkanoyloxymethyl,
1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl, and
the like.
[0151] Similarly, if a compound of Formula I contains an alcohol
functional group, a prodrug can be formed by the replacement of the
hydrogen atom of the alcohol group with a group such as, for
example, (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, --P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate), and the like.
[0152] If a compound of Formula I incorporates --NH-- functional
group, such as in a primary or secondary amine or in a
nitrogen-containing heterocycle, such as imidazole or piperazine
ring, a prodrug can be formed by the replacement of a hydrogen atom
in the amine group with a group such as, for example, R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7) cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl, --C(OH)C(O)OY.sup.1 wherein Y.sup.1 is H,
(C.sub.1-C.sub.6)alkyl or benzyl, --C(OY.sup.2)Y.sup.3 wherein
Y.sup.2 is (C.sub.1-C.sub.4)alkyl and Y.sup.3 is
(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sup.4)Y.sup.5
wherein Y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino morpholino, piperidin-1-yl or
pyrrolidin-1-yl, and the like.
[0153] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective in producing the desired therapeutic,
ameliorative, inhibitory or preventative effect.
[0154] "Capsule" is meant to describe a special container or
enclosure made of methyl cellulose, polyvinyl alcohols, or
denatured gelatins or starch for holding or containing compositions
comprising the active ingredients. Hard shell capsules are
typically made of blends of relatively high gel strength bone and
pork skin gelatins. The capsule itself may contain small amounts of
dyes, opaquing agents, plasticizers and preservatives.
[0155] "Tablet" is meant to describe a compressed or molded solid
dosage form containing the active ingredients with suitable
diluents. The tablet can be prepared by compression of mixtures or
granulations obtained by wet granulation, dry granulation or by
compaction.
[0156] "Oral gels" is meant to describe to the active ingredients
dispersed or solubilized in a hydrophillic semi-solid matrix.
[0157] "Powders for constitution" refers to powder blends
containing the active ingredients and suitable diluents which can
be suspended in water or juices.
[0158] "Diluent" refers to substances that usually make up the
major portion of the composition or dosage form. Suitable diluents
include sugars such as lactose, sucrose, mannitol and sorbitol;
starches derived from wheat, corn, rice and potato; and celluloses
such as microcrystalline cellulose. The amount of diluent in the
composition can range from about 10 to about 90% by weight of the
total composition, preferably from about 25 to about 75%, more
preferably from about 30 to about 60% by weight, even more
preferably from about 12 to about 60%.
[0159] "Disintegrants" refers to materials added to the composition
to help it break apart (disintegrate) and release the medicaments.
Suitable disintegrants include starches; "cold water soluble"
modified starches such as sodium carboxymethyl starch; natural and
synthetic gums such as locust bean, karaya, guar, tragacanth and
agar; cellulose derivatives such as methylcellulose and sodium
carboxymethylcellulose; microcrystalline celluloses and
cross-linked microcrystalline celluloses such as sodium
croscarmellose; alginates such as alginic acid and sodium alginate;
clays such as bentonites; and effervescent mixtures. The amount of
disintegrant in the composition can range from about 2 to about 15%
by weight of the composition, more preferably from about 4 to about
10% by weight.
[0160] "Binders" refers to substances that bind or "glue" powders
together and make them cohesive by forming granules, thus serving
as the "adhesive" in the formulation. Binders add cohesive strength
already available in the diluent or bulking agent. Suitable binders
include sugars such as sucrose; starches derived from wheat, corn
rice and potato; natural gums such as acacia, gelatin and
tragacanth; derivatives of seaweed such as alginic acid, sodium
alginate and ammonium calcium alginate; cellulosic materials such
as methylcellulose and sodium carboxymethylcellulose and
hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics
such as magnesium aluminum silicate. The amount of binder in the
composition can range from about 2 to about 20% by weight of the
composition, more preferably from about 3 to about 10% by weight,
even more preferably from about 3 to about 6% by weight.
[0161] "Lubricant" is meant to describe a substance added to the
dosage form to enable the tablet, granules, etc. after it has been
compressed, to release from the mold or die by reducing friction or
wear. Suitable lubricants include metallic stearates such as
magnesium stearate, calcium stearate or potassium stearate; stearic
acid; high melting point waxes; and water soluble lubricants such
as sodium chloride, sodium benzoate, sodium acetate, sodium oleate,
polyethylene glycols and d'l-leucine. Lubricants are usually added
at the very last step before compression, since they must be
present on the surfaces of the granules and in between them and the
parts of the tablet press. The amount of lubricant in the
composition can range from about 0.2 to about 5% by weight of the
composition, preferably from about 0.5 to about 2%, more preferably
from about 0.3 to about 1.5% by weight.
[0162] "Glidents" means materials that prevent caking and improve
the flow characteristics of granulations, so that flow is smooth
and uniform. Suitable glidents include silicon dioxide and talc.
The amount of glident in the composition can range from about 0.1%
to about 5% by weight of the total composition, preferably from
about 0.5 to about 2% by weight.
[0163] "Coloring agents" refers to excipients that provide
coloration to the composition or the dosage form. Such excipients
can include food grade dyes and food grade dyes adsorbed onto a
suitable adsorbent such as clay or aluminum oxide. The amount of
the coloring agent can vary from about 0.1 to about 5% by weight of
the composition, preferably from about 0.1 to about 1%.
[0164] "Bioavailability" refers to the rate and extent to which the
active drug ingredient or therapeutic moiety is absorbed into the
systemic circulation from an administered dosage form as compared
to a standard or control. Conventional methods for preparing
tablets are known. Such methods include dry methods such as direct
compression and compression of granulation produced by compaction,
or wet methods or other special procedures. Conventional methods
for making other forms for administration such as, for example,
capsules, suppositories and the like are also well known.
[0165] The compounds of Formula I can form salts which are also
within the scope of this invention. Reference to a compound of
Formula I herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula III contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula I may be formed, for example, by reacting
a compound of Formula I with an amount of acid or base, such as an
equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by
lyophilization.
[0166] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[0167] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0168] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0169] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates and prodrugs of the compounds as well as the
salts and solvates of the prodrugs), such as those which may exist
due to asymmetric carbons or sulfurs on various substituents,
including enantiomeric forms (which may exist even in the absence
of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention. For example, if a compound of Formula (I) incorporates a
double bond or a fused ring, both the cis- and trans-forms, as well
as mixtures, are embraced within the scope of the invention.
Individual stereoisomers of the compounds of the invention may, for
example, be substantially free of other isomers, or may be admixed,
for example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present invention can have
the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate" "prodrug"
and the like, is intended to equally apply to the salt, solvate and
prod rug of enantiomers, stereoisomers, rotamers, tautomers,
racemates or prodrugs of the inventive compounds.
[0170] Diasteromeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diasteromeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Also, some of
the compounds of Formula (I) may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of chiral HPLC column.
[0171] Polymorphic forms of the compounds of formula I, and of the
salts, solvates and prodrugs of the compounds of formula I, are
intended to be included in the present invention
[0172] The present invention also embraces isotopically-labelled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine and chlorine, such as .sup.2H, .sup.3H,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
[0173] Certain isotopically-labelled compounds of Formula (I)
(e.g., those labeled with .sup.3H and .sup.14C) are useful in
compound and/or substrate tissue distribution assays. Tritiated
(i.e., .sup.3H) and carbon-.sup.14 (i.e., .sup.14C) isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Isotopically labelled compounds of
Formula (I) can generally be prepared by following procedures
analogous to those disclosed in the Schemes and/or in the Examples
hereinbelow, by substituting an appropriate isotopically labelled
reagent for a non-isotopically labelled reagent.
[0174] The compounds according to the invention have
pharmacological properties; in particular, the compounds of Formula
I can be useful as .alpha.2C adrenoreceptor agonists.
[0175] A preferred dosage is about 0.001 to 500 mg/kg of body
weight/day of the compound of Formula I. An especially preferred
dosage is about 0.01 to 25 mg/kg of body weight/day of a compound
of Formula I, or a pharmaceutically acceptable salt or solvate of
said compound.
[0176] The compounds of this invention may also be useful in
combination (administered together or sequentially) with one or
more therapeutic agents such as, for example, glucocorticosteroids,
PDE-4 inhibitors, anti-muscarinic agents, cromolyn sodium, H.sub.1
receptor antagonists, 5-HT.sub.1 agonists, NSAIDs,
angiotensin-converting enzyme inhibitors, angiotensin II receptor
agonists, .beta.-blockers, .beta.-agonists (including both long and
short acting), leukotriene antagonists, diuretics, aldosterone
antagonists, ionotropic agents, natriuretic peptides, pain
management/analgesic agents, anti-anxiety agents, anti-migraine
agents, and therapeutic agents suitable for treating heart
conditions, psychotic disorders, and glaucoma.
[0177] Suitable steroids include prednisolone, fluticasone
(including all ester such as the propionate or furoate esters),
triamcinolone, beclomethasone, mometasone (including any ester form
such as mometasone furoate), budasamine, ciclesonide betamethasone,
dexamethasone, prednisone, flunisolide, and cortisone.
[0178] Suitable PDE-4 inhibitors include roflumilast, theophylline,
rolipram, piclamilast, cilomilast and CDP-840.
[0179] Suitable antiimuscarinic agents include ipratropium bromide
and tiatropium bromide.
[0180] Suitable H.sub.1 antagonists include astemizole, azatadine,
azelastine, acrivastine, brompheniramine, cetirizine,
chlorpheniramine, clemastine, cyclizine, carebastine,
cyproheptadine, carbinoxamine, descarboethoxyloratidine,
diphenhydramine, doxylamine, dimethindene, ebastine, epinastine,
efletirizeine, fexofenadine, hydroxyzine, ketotifen, loratidine,
levocabastine, meclizine, fexofenadine, hydroxyzine, ketotifen,
loratadine, levocabastine, meclizine, mizolastine, mequitazine,
mianserin, noberastine, norastemizole, picumast, pyrilamine,
promethazine, terfenadine, tripelennamine, temelastine,
trimeprazine or triprolidine.
[0181] Suitable anti-inflammatory agents include aspirin,
diclofenac, diflunisal, etodolac, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, nabumetone, naproxen,
oxaprozin, piroxicam, sulindac, and tolmetin.
[0182] Suitable aldosterone antagonists include spironolactone.
[0183] Suitable ionotropic agents include digitalis.
[0184] Suitable angiotensin II receptor agonists include irbesartan
and losartan.
[0185] Suitable diuretics include spironolactone, methyclothiazide,
bumetanide, torsemide, hydroflumethiazide, trichlormethiazide,
hydroclorothiazide, triamterene, ethacrynic acid, methyclothiazide,
hydrochlorothiazide, benzthiazide, hydrochlorothiazide,
quinethazone, hydrochlorothiazide, chlorthalidone, furosemide,
indapamide, hydroclorothiazide, triamterene, trichlormethiazide,
hydrochlorothiazide, amiloride HCl, amiloride HCl, metolazone,
trichlormethiazide, bendroflumethiazide, hydrochlorothiazide,
polythiazide, hydroflumethiazide, chlorthalidone, and
metolazone.
[0186] Suitable pain management/analgesic agents include Celecoxib,
amitriptyline, ibuprofen, naproxen, gabapentin, tramadol,
rofecoxib, oxycodone HCl, acetaminophenoxycodone HCl,
carbamazepine, amitriptyline, diclofenac, diclofenac, etodolac,
fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac tromethamine, mefenamic acid, meloxicam,
nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin
sodium, valdecoxib, diclofenac/misoprostol, oxycontin, vicodin,
darvocet, percocet, morphine sulfate, dilaudid, stadol, stadol NS,
acetaminophen with codeine, acetaminophen with codeine #4,
Lidoderm.RTM. patches, ziconotide, duloxetine, roboxetine,
gabapentin and pregabalin.
[0187] Suitable .beta.-blockers include acebutolol, atenolol,
atenolol/chlorthalidone, betaxolol, bisoprolol fumarate,
bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol,
propranolol, propranolol/HCTZ, sotalol, and timolol.
[0188] Suitable .beta.-agonists include dobutamine, ritodrine,
salbutamol, levalbuterol, metaproternol, formoterol, fenoterol,
bambuterol, brocaterol, clenbuterol, terbutaline, tulobuterol,
epinephrine, isoprenalin, and hexoprenalin.
[0189] Suitable leucotriene antagonists include levamisole.
[0190] Suitable anti-migraine agents include rovatriptan succinate,
naratriptan HCl, rizatriptan benzoate, sumatriptan succinate,
zolmitriptan, almotriptan malate, methysergide maleate,
dihydroergotamine mesylate, ergotamine tartrate, ergotamine
tartrate/caffeine, Fioricet.RTM., Frominal.RTM., Depakene.RTM., and
Depakote.RTM..
[0191] Suitable anti-anxiety and anti-depressant agents include
amitriptyline HCl, bupropion HCl, citalopram hydrobromide,
clomipramine HCl, desipramine, fluoxetine, fluvoxamine maleate,
maprotiline HCl, mirtazapine, nefazodone HCl, nortriptyline,
paroxetine HCl, protriptyline HCl, sertraline HCl, doxepin, and
trimipramine maleate.
[0192] Suitable angiotensin converting enzyme inhibitors include
Captopril, enalapril, enalapril/HCTZ, lisinopril, lisinopril/HCTZ,
and Aceon.RTM..
[0193] The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological assays.
The exemplified pharmacological assays which are described later
have been carried out with the compounds according to the invention
and their salts.
[0194] This invention is also directed to pharmaceutical
compositions which comprise at least one compound of Formula I, or
a pharmaceutically acceptable salt or solvate of said compound and
at least one pharmaceutically acceptable carrier.
[0195] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18.sup.th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0196] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions or suspensions
for intranasal administration.
[0197] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0198] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0199] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0200] The compounds of this invention may also be delivered
subcutaneously.
[0201] Preferably the compound is administered orally.
[0202] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0203] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 100
mg, preferably from about 1 mg to about 50 mg, more preferably from
about 1 mg to about 25 mg, according to the particular
application.
[0204] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0205] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 500 mg/day,
preferably 1 mg/day to 200 mg/day, in two to four divided
doses.
[0206] Another aspect of this invention is a kit comprising a
therapeutically effective amount of at least one compound of
Formula I, or a pharmaceutically acceptable salt or solvate of said
compound and a pharmaceutically acceptable carrier, vehicle or
diluent.
[0207] Yet another aspect of this invention is a kit comprising an
amount of at least one compound of Formula I, or a pharmaceutically
acceptable salt or solvate of said compound and an amount of at
least one therapeutic agent listed above, wherein the amounts of
the two or more ingredients result in desired therapeutic
effect.
[0208] The invention disclosed herein is exemplified by the
following preparations and examples which should not be construed
to limit the scope of the disclosure. Alternative mechanistic
pathways and analogous structures will be apparent to those skilled
in the art.
[0209] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian VXR-200 (200 MHz, .sup.1H), Varian Gemini-300
(300 MHz), Varian Mercury VX-400 (400 MHz), or Bruker-Biospin
AV-500 (500 MHz), and are reported as ppm with number of protons
and multiplicities indicated parenthetically. Where LC/MS data are
presented, analyses was performed using an Applied Biosystems
API-100 mass spectrometer and C18 column, 10-95%
CH.sub.3CN--H.sub.2O (with 0.05% TFA) gradient. The observed parent
ion is given.
[0210] The following solvents and reagents may be referred to by
their abbreviations in parenthesis:
Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; Ph=phenyl, and
Ac=acetyl
.mu.l=microliters
AcOEt or EtOAc=ethyl acetate
AcOH or HOAc=acetic acid
ACN=acetonitrile
atm=atmosphere
Boc or BOC=tert-butoxycarbonyl
DCM or CH.sub.2Cl.sub.2: dichloromethane:
DIPEA=diisopropylethylamine
DMAP=4-dimethylaminopyridine
DMF=dimethylformamide
DMS=dimethylsulfide
DMSO=dimethyl sulfoxide
EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
Fmoc=9-fluorenylmethoxycarbonyl
g=grams
h=hour
HATU=O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
HOBt=1-hydroxybenzotriazole
LAH=lithium aluminum hydride
LCMS=liquid chromatography mass spectrometry
min=minute
mg=milligrams
mL=milliliters
mmol=millimoles
MCPBA=3-chloroperoxybenzoic acid
MeOH: methanol
MS=mass spectrometry
NMR=nuclear magnetic resonance spectroscopy
RT or rt=room temperature (ambient, about 25.degree. C.).
TEA or Et.sub.3N=triethylamine
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TLC=thin layer chromatography
TMS=trimethylsilyl
Tos or tosyl=p-toluenesulfonyl
Tr=triphenylmethyl
EXAMPLES
[0211] The compounds of this invention can be prepared through the
general approach outlined in Schemes 1 and 2. Scheme 1 shows an
approach in which S1 and S2 are joined together. Examples of these
approaches include reaction of S1 with an electrophilic S2
compound. In various embodiments, R' is an carboxaldehyde (leading
to coupling by reductive amination), a carboxylic acid (leading to
amide coupling) or methylene chloride (leading to coupling by
alkylation). ##STR25##
[0212] According to another embodiment, compound S6 is prepared by
alkylation of S4 with S5. Exemplary procedures employed in the
synthesis of various S1 and S4 fragments are described in the
examples below. ##STR26##
[0213] The starting materials and reagents used in preparing
compounds described are either available from commercial suppliers
such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics
Co. (New Jersey, USA) or were prepared by literature methods known
to those skilled in the art.
[0214] Compounds of formulae S3 and S6 can be prepared by the
general methods outlined above. Exemplary compounds were prepared
as described in the examples below or from starting materials known
in the art. These examples are being provided to further illustrate
the present invention. They are for illustrative purposes only; the
scope of the invention is not to be considered limited in any way
thereby.
Preparative Example 1
[0215] ##STR27## Steps 1-2 ##STR28##
[0216] To a stirred solution of 6-nitroindoline (8.0 g, 48.8 mmol)
in DCM (50 mL) was added pyridine (9.9 mL, 122 mmol), (Boc).sub.2O
(10.6 g, 48.6 mmol) and catalytic DMAP. The mixture was stirred
overnight. Reaction was washed with brine, and the organic layer
was dried (Na.sub.2SO.sub.4), filtered and concentrated.
Chromatography (20% EtOAc/hexanes) provided 1-Boc-6-nitroindoline
(10 g, 78%).
[0217] To a stirred solution of 1-Boc-6-nitroindoline (3.5 g, 13.2
mmol) in MeOH/EtOAc (80 mL/40 mL) was added 10% Pd/C (700 mg). The
reaction was stirred under H.sub.2 (1 atm) overnight. The mixture
was filtered through celite and concentrated to give 1A (3.1 g,
100%). Steps 3-4 ##STR29##
[0218] To a stirred solution of compound 1A (1.33 g, 5.68 mmol) in
dioxane (36 mL) and H.sub.2O (10 mL) at 0.degree. C. was added
Na.sub.2CO.sub.3 (66 g, 6.25 mmol) and Fmoc-Cl (1.61 g, 6.25 mmol).
The reaction was stirred at 0.degree. C. for 1.5 h and then at RT
for 1 h. Solvent was removed under reduced pressure and the residue
was partitioned between H.sub.2O (50 mL) and DCM (50 mL). The
aqueous phase was extracted with DCM (50 mL). The combined organic
layer was dried (Na.sub.2SO.sub.4), filtered and concentrated under
reduced pressure. The residue was purified by chromatography
(10-30% EtOAc/hexanes) to give 2.31 g (90%). This compound was
stirred in 30% TFA/DCM (50 mL) for 0.5 h. Solvent was removed under
reduced pressure and sat. NaHCO.sub.3 solution was added (50 mL).
The mixture was extracted with DCM (3.times.50 mL). The combined
organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated to give 1B (1.6 g, 80%). Step 5 ##STR30##
[0219] The resin bound imidazole-4-carboxyaldehyde (1C) was
prepared as follows: 2-Chlorotrityl chloride resin (1 g, 1.1 to 1.6
mmole/g, Novabiochem, 100-200 mesh, 1% DVB) was suspended in dry
DMF (5 mL) and 1,2-dichloroethane (5 mL), followed by addition of
4-imidazolecarboxyaldehyde (0.28 g, 3.3 mmol) and TEA (0.46 mL, 3.3
mmole). The mixture was shaken overnight. The resin was filtered
and washed with DMF (3.times.10 mL), MeOH (3.times.10 mL), and DCM
(4.times.10 mL) and dried under high vacuum overnight.
##STR31##
[0220] To a suspension of resin 1C (0.3 g, 0.42 mmol) and 1B (0.6
g, 1.68 mmol) in 1,2-dichloroethane (8 mL) and
N,N-dimethylacetamide (2 mL) was added NaBH(OAc).sub.3 (0.71 g,
3.36 mmol). The mixture was shaken overnight. The resin was
filtered and washed with DMF (3.times.10 mL), MeOH (3.times.10 mL),
and DCM (4.times.10 mL) to give resin 1D. ##STR32##
[0221] A small amount of resin 1D (10 mg) was cleaved in 50%
TFA/DCM for 1 h. The resin was filtered and the filtrate was
concentrated under reduced pressure and the residue was identified
in LC-MS as a single peak as the desired cleavage product 1E. MS
m/z 437 (MH+). Steps 6-8 ##STR33##
[0222] Resin 1D (25 mg) was shaken in 30% piperidine/DMF (5 mL) for
2 h. The resin was filtered and washed with DMF (3.times.10 mL),
MeOH (3.times.10 mL), and DCM (4.times.10 mL). The resin was then
suspended in DCM (4 mL) and MeNCO (0.1 g) was added. The mixture
was shaken overnight. The resin was washed with DCM (3.times.10
mL), MeOH (3.times.10 mL), and DCM (4.times.10 mL) to give resin
1F.
[0223] Resin 1F was cleaved in 50% TFA/DCM (10 mL) for 3 h and
filtered. The filtrate was concentrated under reduced pressure to
give the title compound 1 as a TFA salt. MS m/z 272 (MH+).
[0224] Compounds in Table 1 were prepared similarly as described
above, by deprotecting resin 1D and then capping with different
reagents as shown in the table. After cleavage from the resin, the
final compound can be purified further by Gilson HPLC(YMC COMBI
PREP ODS-AQ 50.times.20 mm I.D. with 5 micron particle size, 20
mL/min, 10 min gradient: 10-90% ACN: H.sub.2O with 0.1% TFA).
Alternatively, compound 1G and 1H can be prepared by following
procedure as described in Example 4. Compound 1, 1I and 1J can also
be prepared by following procedure as described in Example 5.
TABLE-US-00001 TABLE 1 ##STR34## MS Cpd Reagent R (MH+) 1G
ClCO.sub.2Me Pyridine ##STR35## 273 1H Ac.sub.2O Pyridine ##STR36##
257 1I Me.sub.3SiNCO ##STR37## 258 1J CH.sub.3SO.sub.2Cl DIPEA
##STR38## 371
Preparative Example 2
[0225] ##STR39## Step 1 ##STR40##
[0226] To a stirred solution of 1H-indole-6-carboxylic acid (1.5 g,
9.31 mmol) in MeOH (200 mL) was added conc. H.sub.2SO.sub.4 (3 mL).
The reaction was refluxed for 15 h and cooled to RT. The mixture
was neutralized with sat. NaHCO.sub.3 and MeOH was removed under
reduced pressure. The remaining mixture was extracted with EtOAc
(50 mL.times.3). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. Chromatography (20% EtOAc/hexanes) provided 2A (1.4 g,
88%) as a white solid. Step 2 ##STR41##
[0227] A stirred solution of 2A (1 g, 5.7 mmol) in DCM (20 mL) and
TFA (10 mL) at -20.degree. C. was treated with Et.sub.3SiH (10 mL).
The reaction was warmed to RT slowly and stirred thereafter for 17
h. The reaction was quenched with 2 N NaOH until pH 8. The mixture
was extracted with DCM (100 mL.times.3). The combined organic layer
was dried (Na.sub.2SO.sub.4), filtered and concentrated under
reduced pressure. Chromatography (20% EtOAc/hexanes) provided 2B
(0.5 g, 49%). Step 3 ##STR42##
[0228] In a manner similar to that found in Example 1, Step 5, 2B
and resin 1C were converted to resin 2C. Step 4 ##STR43##
[0229] Resin 2C (0.16 g) was treated with 8 mL of a solution
prepared by dissolving KOH (7.2 g) in H.sub.2O (2 mL)/MeOH (60
mL)/dioxane (60 mL). The mixture was shaken overnight. The resin
was filtered and washed with dioxane (3.times.10 mL), MeOH
(3.times.10 mL), DCM (4.times.10 mL) and pumped on high vacuum to
give resin 2D. ##STR44##
[0230] A small amount of resin 2D (10 mg) was cleaved in 50%
TFA/DCM for 1 h. The resin was filtered and the filtrate was
concentrated under reduced pressure and the residue was identified
in LC-MS as the desired cleavage product 2E: MS m/z 271 (MH+).
Steps 5-6 ##STR45##
[0231] Resin 2D (0.1 g, 0.16 mmol) was suspended in 1:1 DCM:DMF (3
mL) and treated with MeNH.sub.2 (2 M/THF, 0.5 mL), EDCI (0.16 mL, 1
mmol) and HOBt (0.074 g, 0.48 mmol). The mixture was shaken
overnight. The resin was filtered and washed with DMF (3.times.10
mL), MeOH (3.times.10 mL), and DCM (4.times.10 mL) to give resin
2F.
[0232] In a manner similar to that found in Example 1, Step 8, 2F
was converted to the title compound 2. MS m/z 257 (MH+).
[0233] Compounds in Table 2 can be prepared similarly as described
above starting from resin 2D, by coupling with different reagents
as shown in the table. If needed, the final compounds can be
further purified as described in Example 1. TABLE-US-00002 TABLE 2
##STR46## Cpd reagent R MS (MH+) 2G NH.sub.4Cl NH.sub.2 243 DIPEA
2H ##STR47## ##STR48## 314 2I ##STR49## ##STR50## 301 2J Me.sub.2NH
##STR51## 271 2K morpholine ##STR52## 313
Preparative Example 3
[0234] ##STR53## Step 1 ##STR54##
[0235] Chlorosulfonic acid (5 g, 42.9 mmol) was cooled in an ice
bath and treated with 1-(5-bromoindolin-1-yl)ethanone (2.4 g, 10
mmol). The reaction was stirred at 0.degree. C. for 20 min and then
heated to 70.degree. C. for 7 h. After cooling, the mixture was
slowly poured onto ice. The precipitate was filtered, washed with
H.sub.2O and pumped on high vacuum overnight to give a crude
mixture containing compound 3A and starting material in ratio of
2:3 as determined by .sup.1H NMR. Step 2 ##STR55##
[0236] One third of the above mixture was dissolved in DCM (10 mL)
and treated with MeNH.sub.2 (2 M/THF, 5 mL). The reaction was
stirred at RT overnight, concentrated, and partitioned between
EtOAc and water. The aqueous layer was extracted with EtOAc
(2.times.100 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated. Chromatography
(60-100% EtOAc/hexanes) provided 3B (0.39 g). Step 3 ##STR56##
[0237] To Compound 3B (0.39 g, 1.17 mmol) was added 37% HCl (10 mL)
and the mixture was refluxed for 1.5 h. The reaction was cooled and
diluted with H.sub.2O, then basified with 2 N NaOH. After
extraction with EtOAc (2.times.50 mL), the organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated to give 3C (0.26 g,
76%). Steps 4-5 ##STR57##
[0238] In a manner similar to that found in Example 1, Steps 5 and
8, 3C was converted to compound 3D. MS m/z 371 (MH+).
Alternatively, 3C can be reacted with 4-imidazolecarboxaldehyde and
converted to 3D as described in Example 4, Step 1.
Step 6
[0239] A mixture of 3D (0.14 g, 0.37 mmol) and 10% Pd/C (20 mg) in
MeOH (10 mL) was hydrogenated at 50 psi H.sub.2 overnight and
filtered through celite. The filtrate was concentrated under
reduced pressure. The residue was purified by Glison 215 HPLC (YMC
COMBI PREP ODS-AQ 50.times.20 mm I.D. with 5 micron, 20 mL/min, 10
min gradient: 10-90 ACN/H.sub.2O with 0.1% TFA) to give the title
compound 3. MS m/z 293 (MH+).
[0240] Compounds in Table 3 can be prepared similarly as described
above starting from compound 3A, by coupling with different amines
as shown in the table. TABLE-US-00003 TABLE 3 ##STR58## MS Cpd
reagent R.sub.1 R.sub.2 (MH+) 3E NH.sub.3/MeOH NH.sub.2 H 279 3F
Me.sub.2NH/THF NMe.sub.2 Br 385 3G Me.sub.2NH/THF NMe.sub.2 H
307
Preparative Example 4
[0241] ##STR59## Steps 1-2 ##STR60##
[0242] To a stirred solution of 4A (5 g, 30 mmol) in
1,2-dichloroethane (100 mL) was added 4-imidazolecarboxaldehyde
(2.9 g, 30 mmol) and HOAc (3 mL). The mixture was stirred for 1 h,
and NaBH(OAc).sub.3 (13 g, 61 mmol) was added. The reaction was
stirred overnight at RT, and washed with NaHCO.sub.3 and brine. The
organic layer was dried (MgSO.sub.4), filtered and concentrated (7
g, 94%).
[0243] The resulting product was hydrogenated in a manner similar
to that found in Example 1, Step 2, to provide 4B.
Step 3
[0244] To compound 4B (0.43 g, 2 mmol) in DCM (10 mL) was added TEA
(0.7 mL, 5 mmol) and EtCOCl (0.35 mL, 4 mmol). The mixture was
stirred at RT for 1.5 h. After adding 2 N NaOH, the mixture was
extracted with DCM (3.times.30 mL). The organic layer was dried
(MgSO.sub.4), filtered and concentrated. Chromatography (2-5% of 7N
NH.sub.3-MeOH/DCM) provided the title compound 4 (0.173 g). MS m/z
271 (MH+).
[0245] Compounds in Table 4 were prepared in a similar fashion
starting from compound 4B: TABLE-US-00004 TABLE 4 ##STR61## Cpd R
Spectral data 4C ##STR62## MS 285 (MH+) 4D ##STR63## MS 285 (MH+)
4E ##STR64## MS 309 (MH+) 4F ##STR65## MS 319 (MH+) 4G ##STR66## MS
300 (MH+) 4H ##STR67## .sup.1H NMR(CD.sub.3OD): 7.61 (s, 1H), 6.96
(d, 3H), 6.80 (d, 1H), 4.22 (s, 2H), 4.0 (s, 2H), 3.45 (s, 3H),
3.34 (t, 2H), 2.85 (t, 2H)
Preparative Example 5
[0246] ##STR68## Step 1 ##STR69##
[0247] To a stirred solution of 1A (0.96 g, 4.1 mmol) in DCM (50
mL) was added pyridine (0.33 mL, 4.1 mmol) and methanesulfonic
anhydride (0.71 g, 4.1 mmol). The reaction was stirred for 5 h at
RT. Water was added and the mixture was extracted with DCM
(3.times.50 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. Chromatography (30% EtOAc/hexanes) provided 5A (1.2 g,
94%). Steps 2-4 ##STR70##
[0248] To a stirred solution of 5A (0.73 g, 2.34 mmol) in 1 M NaOH
(10 mL) was added MeI (0.44 mL). The mixture was stirred overnight,
diluted with water (20 mL) and extracted with DCM (3.times.30 mL).
The combined organic layer was dried (Na.sub.2SO.sub.4), filtered
and concentrated under reduced pressure. The residue was then
deprotected and converted to 5B in a manner similar to that found
in Example 1, Step 4 and Example 4, Step 1. MS m/z 307 (MH+).
[0249] The following compounds can be prepared by reacting compound
1A with ethyl chloroformate, N,N-dimethylsulfamoyl chloride or
methanesulfonic anhydride, respectively, followed by
Boc-deprotection and reductive alkylation. TABLE-US-00005 TABLE 5
##STR71## Cpd R MS (MH+) 5C ##STR72## 287 5D ##STR73## 322 5E
##STR74## 293
Preparative Example 6
[0250] ##STR75## Step 1 ##STR76##
[0251] In a manner similar to that found in Example 4, Step 1,
6-nitroindoline was reacted with 1-tritylimidazole-4-carboxaldehyde
and converted to 6A. Step 2 ##STR77##
[0252] A mixture of 6A (3.0 g, 6.2 mmol) in EtOH was treated with
10% Pd/C and hydrogenated at 50 psi H.sub.2 for 4 h. The reaction
was filtered through celite and concentrated to provide the 6B as
tan foam (2.75 g, 98%). Step 3 ##STR78##
[0253] A solution of 6B (1.1 g, 2.4 mmol) in ethyl formate was
refluxed overnight. The reaction was concentrated to one-third
volume, diluted with CH.sub.2Cl.sub.2 and washed with saturated
aqueous NaHCO.sub.3. The organic layers was washed with brine and
concentrated. Chromatography (30-100% EtOAc/hexanes) provided 6C as
a yellow foam (0.41 g, 35%). Steps 4-5 ##STR79##
[0254] A solution of 6C (0.17 g, 0.35 mmol) in THF (10 ml) was
added slowly to a slurry of LAH (0.13 g, 3.5 mmol) in THF (10 ml).
The reaction was refluxed for 1 h, cooled with an ice bath, and
quenched slowly with water and then 10% aqueous NaOH. The mixture
was diluted with EtOAc, filtered through celite and concentrated to
provide a tan brown film. This material was then refluxed overnight
in butyl formate. Chromatography (0-5% 7 N
NH.sub.3-MeOH/CH.sub.2Cl.sub.2) provided 6D as a yellow film (0.020
g, 11%).
[0255] A solution of 6D (0.014 g, 0.03 mmol) in CH.sub.2Cl.sub.2 (3
mL) was treated with Et.sub.3SiH (9 .mu.L, 0.03 mmol) and TFA (28
.mu.L, 0.3 mmol) and stirred at 20.degree. C. for 2 h.
Chromatography (5% 7 N NH.sub.3-MeOH/CH.sub.2Cl.sub.2) provided the
title compound 6 as a yellow film (0.006 g, 85%). LMCS m/z 257
(MH+).
Preparative Example 7
[0256] ##STR80## Step 1 ##STR81##
[0257] A sample of Ac.sub.2O (9.71 mL, 103 mmol) was cooled at
0.degree. C. and treated with HCO.sub.2H (3.95 mL, 103 mmol)
dropwise. The mixture was stirred at 0.degree. C. for 5 min, and
then heated at 55.degree. C. for 2 h. The reaction was cooled to
0.degree. C. and a solution of 1A (9 g, 38.4 mmol) in THF (100 mL)
was added. The mixture was stirred at 0.degree. C. for 30 min, and
the solvent was removed under reduced pressure to yield 7A. Step 2
##STR82##
[0258] Compound 7A was dissolved in THF (100 mL), treated with 2M
BH.sub.3--SMe.sub.2 in THF (77 mL, 142.8 mmol) and refluxed for 2
h. The reaction was then treated with MeOH and refluxed for 10 min.
The mixture was then cooled to RT and concentrated under reduced
pressure. The residue was dissolved in water and extracted with
EtOAc (3.times.120 mL). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated give 7B (8.85 g,
93%). Steps 3-5 ##STR83##
[0259] A solution of 7B (0.26 g, 1.05 mmol) in THF (10 mL) was
treated with MeNCO (0.072 g, 1.26 mmol), stirred overnight, and
concentrated to give 7C.
[0260] In a manner similar to that found in Example 1, Step 4 and
Example 4, Step 1, 7C was deprotected and converted to the title
compound 7. MS m/z 286 (MH+).
[0261] Compounds 7D-7N in TABLE 6 can be prepared starting from
compound 7B, by reaction with isocyanates, acid chlorides or
chloroformates, followed by deprotection and reductive alkylation
as described above. TABLE-US-00006 TABLE 6 ##STR84## Cpd R MS (MH+)
7D ##STR85## 287 7E ##STR86## 272 7F ##STR87## 271 7G ##STR88## 285
7H ##STR89## 301 7I ##STR90## 315 7J ##STR91## 348 7K ##STR92## 300
7L ##STR93## 300 7M ##STR94## 336 7N H 229 ##STR95## ##STR96##
[0262] In a manner similar to that found in Example 1, Step 4 and
Example 4, Step 1, 7A was deprotected and converted to 7O. MS m/z
243 (MH+). Compound 7O was then reduced by BH.sub.3-Me.sub.2S as
described in Example 7, Step 2, to give compound 7N.
Preparative Example 8
[0263] ##STR97## Step 1 ##STR98##
[0264] In a manner similar to that found in Example 4, Step 3, 1A
was reacted with 5-chlorovaleryl chloride to give 8A. Step 2
##STR99##
[0265] A stirred solution of compound 8A (3.1 g, 8 mmol) in THF (10
mL) was treated with 5 N NaOH (100 mL) and stirred overnight. The
mixture was extracted with DCM (2.times.100 mL). Combined organic
layer was dried (Na.sub.2SO.sub.4), filtered and concentrated under
reduced pressure. Chromatography (30% EtOAc/hexanes) provided 8B
(1.73 g, 68%) and recovered 8A (1.2 g). Steps 3-5 ##STR100##
[0266] In a manner similar to that found in Example 1, Step 4 and
Example 4, Step 1, 8B was deprotected and converted to 8C (MS m/z
297 MH+). 8C was then reacted with BH.sub.3-THF in a manner similar
to that found in Example 7, Step 2 to provide the title compound 8.
MS m/z 283 (MH+).
Preparative Example 9
[0267] ##STR101## Step 1 ##STR102##
[0268] In a manner similar to that found in Example 4, Step 3, 1A
was reacted with 2-chloroethyl chloroformate to provide 9A. Steps
2-4 ##STR103##
[0269] To a stirred solution of compound 9A (0.41 g, 1.2 mmol) in
DMF (5 mL) was added NaH (0.1 g, 60% in oil). The mixture was
stirred overnight. Solvent was removed under high vacuum and EtOAc
(20 mL) was added. The mixture was washed with 1 M HCl quickly,
dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(5% MeOH/DCM) to give 9B (0.23 g).
[0270] In a manner similar to that found in Example 1, Step 4 and
Example 4, Step 1, 9B was deprotected and converted to the title
compound 9. MS m/z 285 (MH+).
Preparative Example 10
[0271] ##STR104## Steps 1-2 ##STR105##
[0272] To a stirred solution of 1-hydroxy-6-methylsulfonylindole
10A (1.5 g, 7.1 mmol) in TFA (20 mL) was added 1 M BH.sub.3-THF (20
mL). The reaction was stirred at RT for 30 min. The reaction was
concentrated and treated with 1N NaOH. The mixture was extracted
with DCM (3.times.50 mL). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. Flash chromatography (30-50% EtOAc/hexanes) provided 10B
(1.05 g, 75%).
[0273] In a manner similar to that found in Example 4, Step 1, 10B
was reacted with 4-imidazolecarboxaldehyde to provide the title
compound 10. MS m/z 278 (MH+).
Preparative Example 11
[0274] ##STR106## Step 1 ##STR107##
[0275] To a suspension of KH (30% in mineral oil, washed with
hexanes, 0.68 g, 5.1 mmol) in anhydrous THF (10 mL) at 0.degree. C.
under argon was added a solution of 11A (1 g, 5.1 mmol) in THF (10
mL). After 15 min, the solution was cooled to -78.degree. C. and
treated with t-BuLi (1.7 M in pentane, 6 mL, 10 mmol) dropwise.
After 15 min (-78.degree. C.), DMS (0.92 mL, 10.2 mmol) was added
dropwise. The solution was warmed gradually to RT and stirred
overnight. Then the reaction was carefully quenched by saturated
NH.sub.4Cl (15 mL) and filtered. The filtrate was diluted with
water and extracted with EtOAc (3.times.50 mL). The combined
organic layers were dried (MgSO.sub.4), filtered, and concentrated
under vacuum. The residue was purified by flash column
chromatography (5-25% EtOAc/hexanes) to give compound 11B (1.2 g).
Steps 2-3 ##STR108##
[0276] In a manner similar to that found in Example 10, Step 1, and
Example 4, Step 1, 11B was reduced with BH.sub.3-THF and then
converted to 11C. MS m/z 246 (MH+). Step 4 ##STR109##
[0277] To a stirred solution of compound 11C (0.69 g, 2.82 mmol) in
DCM (50 mL) cooled at 0.degree. C. was added MCPBA (0.63 g, 2.8
mmol). The reaction was stirred for 5 min and 1 N NaOH (10
mL)/H.sub.2O (20 mL) was added. The mixture was extracted with DCM
(3.times.50 mL). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. Chromatography (2-5% 7N NH.sub.3-MeOH/DCM) provided 11
(0.183 g, 25%). MS m/z 262 (MH+).
Preparative Example 12
[0278] ##STR110## Steps 1-2 ##STR111##
[0279] 1-Acetyl-6-cyanoindoline (2.4 g, 12.9 mmol, Tetrahedron,
1967, 23, 3823) was stirred in a solution containing 5 N NaOH (20
mL), MeOH (60 mL) and dioxane (60 mL). The mixture was stirred at
RT over the weekend. Solvent was removed under reduced pressure and
the residue was partitioned between water (100 mL) and DCM (100
mL). Aqueous layer was extracted with DCM (2.times.75 mL). Combined
organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure. Chromatography (10-30%
EtOAc/hexanes) provided 6-cyanoindoline (0.95 g, 51%) which was
then converted to 12A in a manner similar to that found in Example
4, Step 1. Step 3 ##STR112##
[0280] To a stirred solution of compound 12A (0.1 g, 0.45 mmol) in
MeOH (60 mL) was bubbled in HCl gas at 0.degree. C. for 15 min. The
reaction was stirred overnight and solvent was removed under
reduced pressure. The residue was dissolved in 2N NH.sub.3/MeOH (50
mL) and stirred for 4 h. The mixture was concentrated and subjected
to chromatography (DCM containing 5-15% of 7N NH.sub.3/MeOH) to
give the title compound 12 (0.062 g, 57%). MS m/z 242 (MH+).
##STR113##
[0281] Compound 12B can be prepared from compound 12A as follows:
To a stirred solution of 12A (0.197 g, 0.88 mmol) in EtOH (100 mL)
was added NH.sub.2OH (50% in H.sub.2O, 0.5 mL, 15 mmol). The
reaction was refluxed for 24 h. The mixture was concentrated and
subjected to chromatography (DCM containing 10-15% of 7N
NH.sub.3/MeOH) to give 12B (0.22 g, 98% yield). MS m/z 258 (MH+).
##STR114##
[0282] Compound 12C can be prepared from compound 12A as follows:
Compound 12A (0.1 g, 0.44 mmol) was dissolved in EtOH (2 mL) and
methylamine (40% in H.sub.2O, 1 mL) was added. The mixture was
refluxed overnight. Solvent was removed under reduced pressure and
the residue was purified by HPLC (using Waters SunFire.TM. Prep C18
5 .mu.M, 19-100 mm column, gradient: 5-90% H.sub.2O/CH.sub.3CN) to
give 12C (0.028 g, 25%). MS m/z 256 (MH+). ##STR115##
[0283] Compound 12D can be prepared from compound 12A as follows:
To a stirred solution of compound 12A (0.3 g, 1.34 mmol) in MeOH
(30 mL) was bubbled in HCl gas at 0.degree. C. for 15 min. The
reaction was stirred overnight and solvent was removed under
reduced pressure. The residue was dissolved in MeOH (30 mL),
treated with TEA (3.4 mL, 24 mmol) and O-methylhydroxylamine
hydrochloride (2 g, 24 mmol), and stirred for 24 h. Solvent was
removed under reduced pressure and the residue was purified
(reverse phase HPLC) to give 12D (0.16 g, 44%). MS m/z 272
(MH+).
Preparative Example 13
[0284] ##STR116## Steps 1-2 ##STR117##
[0285] In a manner similar to that found in Example 4, Step 1, 2B
was reacted with 4-imidazolecarboxaldehyde to provide 13A. A
mixture of compound 13A (0.075 g, 0.3 mmol), 1,2-aminoethane (0.067
mL) and AlMe.sub.3 (2M in toluene, 0.5 mL) was refluxed overnight.
The reaction was concentrated and purified by preparative HPLC (as
described previously) to give the title compound 13. MS m/z 268
(MH+).
Preparative Example 14
[0286] ##STR118## Step 1 ##STR119##
[0287] To a stirred solution of compound 14A (0.28 g, 1.93 mmol) in
THF (10 mL) was added TMS-CF.sub.3 (0.5 M in THF, 3.8 mL, 1.9 mmol)
and CsF (0.61 g, 4 mmol). The reaction was stirred at RT for 4 h.
Solvent was removed under reduced pressure and H.sub.2O (10 mL) was
added. The aqueous mixture was extracted with EtOAc (3.times.15
mL). The combined organic layer was dried (Na.sub.2SO.sub.4),
filtered and concentrated to give crude 14B. .sup.19F NMR (CDCl3):
78.78 (d). Steps 2-3 ##STR120##
[0288] To a stirred solution of compound 14B (0.2 g, 0.7 mmol) in
DCM (25 mL) was added NaCNBH.sub.3 (0.3 g, 4.76 mmol) and AcOH (0.1
mL). The reaction was stirred overnight and quenched with sat.
NaHCO.sub.3. The aqueous layer was extracted with EtOAc (20
mL.times.3). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated to give 14C.
[0289] In a manner similar to that found in Example 4, Step 1, 14C
reacted with 4-imidazolecarboxaldehyde to provide the title
compound 14. MS m/z 298 (MH+).
Preparative Example 15
[0290] ##STR121## Step 1 ##STR122##
[0291] A stirred solution of 3-fluorophenylacetic acid (10.1 g,
65.5 mmol) in concentrated H.sub.2SO.sub.4 (20 mL) was treated with
a solution of HNO.sub.3 (90%, 12 mL) and conc. H.sub.2SO.sub.4 (15
mL) dropwise through an addition funnel while maintaining a
temperature between 20-35.degree. C. by water bath. The reaction
was stirred overnight at 35.degree. C. and then poured onto ice.
The precipitate was filtered, washed with water, and then dried
under vacuum at 80.degree. C. for 5 h. The solid was dissolved in
MeOH and 0.5 mL conc. H.sub.2SO.sub.4 was added. The reaction was
refluxed for 5 h and cooled to RT overnight. The mixture was cooled
in an ice bath and 3 N NaOH was added until pH=5 was obtained. The
mixture was concentrated under reduced pressure, diluted with
water, and extracted with EtOAc. The combined organic layer was
dried (MgSO.sub.4), filtered and concentrated. Chromatography
(5-20% EtOAc/hexanes) provided 15A (40%). Step 2 ##STR123##
[0292] To a stirred solution of compound 15A (6.83 g, 26.5 mmol) in
MeOH (80 mL) was added 10% Pd/C (0.68 g). The reaction was stirred
under H.sub.2 (1 atm) overnight. The mixture was filtered through
celite and the solvent was removed under reduced pressure to give
5.05 g of the hydrogenation product (96%). This material was
dissolved in 10% HCl (50 mL) and the mixture was refluxed for 0.5
h. The reaction was cooled to RT, basified with 50% NaOH to pH=8,
and extracted with EtOAc (3.times.100 mL). The combined organic
layer was dried (MgSO.sub.4), filtered and concentrated to give 15B
(3.92 g, 93%). Steps 3-4 ##STR124##
[0293] To a suspension of compound 15B (0.305 g, 1.84 mmol) was
added pyridine (0.3 mL, 3.68 mmol) and ClCO.sub.2Me (0.24 mL, 3.11
mmol) The reaction was stirred at RT for 2 h and the precipitate
was filtered. The precipitate was washed with DCM, sat. NH.sub.4Cl,
H.sub.2O, and 3 N HCl. The DCM layer was dried (MgSO.sub.4),
filtered and concentrated and combined with the precipitate (dried
on high vacuum) to give 0.455 g of the corresponding
methylcarbamate. The solid was dissolved in THF (10 mL) and
BH.sub.3--SMe.sub.2 (2 M/THF, 1.84 mL, 3.68 mmol) was added. The
reaction was refluxed for 3 h, quenched with MeOH, and refluxed for
another 10 min. Solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (10-25%
EtOAc/hexanes) to give 15C (0.24 g, 63%).
[0294] Compound 15C was reacted with 4-imidazolecarboxaldehyde to
provide the title compound 15 in a manner similar to that described
in Example 4, Step 1. MS m/z 291 (MH+) ##STR125##
[0295] Compound 15D can be prepared starting from compound 15B, by
using methanesulfonic anhydride/pyridine, followed by BH.sub.3
reduction and reductive alkylation with 4-imidazolecarboxyaldehyde
as described previously. MS m/z 311, (MH+) ##STR126##
[0296] Compound 15E (MS m/z 307, MH+) can be prepared starting from
3-chlorophenylacetic acid using an approach similar to that
described in Example 15, except that Step 2 (nitro group reduction)
was accomplished using Raney Ni as described below: To a stirred
solution of 3-chloro-4,6-dinitrophenylacetic acid in EtOH was added
Raney Ni. The reaction was stirred under H.sub.2 (1 atm) for 4 h.
The mixture was filtered through celite and solvent was removed
under reduced pressure. This material was dissolved in 10% HCl (10
mL) and the mixture was refluxed for 0.5 h. The reaction was cooled
to RT, basified with 50% NaOH to pH=8, and extracted with EtOAc (30
mL.times.5). Combined organic layer was dried (Na.sub.2SO.sub.4),
filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography (60-80% EtOAc/hexanes).
Preparative Example 16
[0297] ##STR127## Steps 1-2 ##STR128##
[0298] In a manner similar to that found in Example 15, Steps 3-4,
15B was reacted with benzylchloroformate and then reduced with
BH.sub.3--SMe.sub.2 to provide 16A. Steps 3-4 ##STR129##
[0299] In a manner similar to that found in Example 1, Steps 1-2,
16A was protected and then hydrogenated to provide 16B. Steps 5-7
##STR130##
[0300] To a stirred solution of compound 16B (170 mg, 0.67 mmol) in
DCM (10 mL) was added pyridine (0.11 mL, 1.34 mmol) and Ac.sub.2O
(0.076 mL, 0.8 mmol). The reaction was stirred for 1 h, then
additional Ac.sub.2O (0.02 mL) was added. The reaction was stirred
overnight and concentrated. The residue was diluted with water and
extracted with EtOAc (3.times.30 mL). The combined organic layer
was washed with NH.sub.4Cl and water. The organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated to give compound 16C
(200 mg, 100%). In a manner similar to that found in Example 1,
Step 4 and Example 4, Step 1, 16C was deprotected and converted to
the title compound 16. MS m/z 275 (MH+).
[0301] The compounds 16D and 16E (Table 7) can be prepared starting
from compound 16B, using methylisocyanate or
N,N-dimethylsulfamoylchloride/2,6-lutidine, followed by
Boc-deprotection and reductive alkylation as described above.
Compound 16F (Table 7) can be prepared from compound 16A by
performing reductive alkylation with 4-imidazolecarboxyaldehyde and
hydrogenation to remove the Cbz group, as described above.
TABLE-US-00007 TABLE 7 ##STR131## Cpd R MS (MH+) 16D ##STR132## 290
16E ##STR133## 340 16F H 233
Preparative Example 17
[0302] ##STR134## Steps 1-5 ##STR135##
[0303] In a manner similar to that found in Example 7 (Steps 1-2)
16B was converted to 17A. 17A was then reacted with ClCO.sub.2Me,
deprotected and converted to the title compound 17 in a manner
similar to that found in Example 15 (Step 3), Example 1 (Step 4)
and Example 4 (Step 1). MS m/z 305 (MH+).
[0304] The following compounds (TABLE 8) can be prepared by
treating compound 17A with Ac.sub.2O, methanesulfonic anhydride,
N,N-dimethylsulfamoyl chloride or MeNCO respectively, followed by
Boc-deprotection and reductive alkylation as described previously.
TABLE-US-00008 TABLE 8 ##STR136## Cpd R MS (MH+) 17B ##STR137## 289
17C ##STR138## 325 17D ##STR139## 354 17E ##STR140## 304
Preparative Example 18
[0305] ##STR141## Steps 1-2 ##STR142##
[0306] In a manner similar to that found in Example 16, Step 5, and
Example 3, Step 1, 18A was sequentially treated with Ac.sub.2O and
chlorosulfonic acid to provide 18B. Step 3-5 ##STR143##
[0307] A stirred solution of Na.sub.2SO.sub.3 (1.15 g, 9.15 mmol)
and Na.sub.2HCO.sub.3 (0.81 g, 9.63 mmol) in H.sub.2O (16 mL) at
80.degree. C. was treated with 18B (1.33 g, 4.82 mmol). The mixture
was stirred at 80.degree. C. for 1 h, and then allowed to cool to
RT and stand overnight. The reaction was concentrated and then
residue dried under high vacuum. To this residue was carefully
added NaHCO.sub.3 (0.77 g, 9.15 mmol) and dimethyl sulfate (0.69
mL, 7.33 mmol), while water was added through addition funnel to
keep the reaction mixture stirring. The reaction was heated at
reflux over the weekend. After the mixture was cooled to 75.degree.
C., benzene (5 mL) was added. The mixture was stirred briefly,
cooled to RT, and ammonia was added. After solvent was removed
under reduced pressure, the residue was mixed with 2N NaOH and
extracted with EtOAc (3.times.50 mL). The organic layer was dried
(MgSO.sub.4), filtered, and concentrated under reduced pressure.
Chromatography (0-5% MeOH/DCM) provided 18C (0.399 g, 32%).
[0308] In a manner similar to that found in Example 3, Step 3, and
Example 4, Step 1, 18C was deprotected and converted to the title
compound 18. MS m/z 296 (MH+).
Preparative Example 19
[0309] ##STR144## Step 1 ##STR145##
[0310] To a stirred solution of compound 19A (0.86 g, 2.76 mmol,
Tetrahedron, 2002, 58, 3605) in DMSO (10 mL) was added sodium
sulfinate (0.37 g, 3.64 mmol) and cupper triflate benzene complex
(42 mg, 0.083 mmol). The mixture was stirred for 5 min and a
solution of N,N'-dimethylethylene-diamine (0.32 mL, 3 mmol) in DMSO
(3 mL) was added. The reaction was heated at 110.degree. C. for 12
h and then concentrated. The residue was purified by flash column
chromatography (10% MeOH/DCM) to give compound 19B (0.6 g, 81%
yield). Step 2 ##STR146##
[0311] To a stirred solution of compound 19B (0.1 g, 0.38 mmol) in
DMF (15 mL) was added NaH (0.08 g). The mixture was stirred for 5
min, and compound 19C (0.1 g, J. Med. Chem. 2002, 45, 533) was
added. The reaction was stirred for 24 h. Solvent was removed under
high vacuum and the residue was purified by flash column
chromatography (20% EtOAc/DCM) to give 19D (0.08 g, 36% yield).
Step 3
[0312] Compound 19D was dissolved in EtOH (10 mL) and treated with
10% Pd/C (10 mg). The reaction was stirred under H.sub.2 (1 atm) at
45.degree. C. for 16 h. The mixture was filtered through celite and
the filtrate was concentrated. The residue was purified by flash
column chromatography (10% MeOH/DCM) to give the title compound 19
(30 mg, 63%). MS m/z 344 (MH+).
Preparative Example 20
[0313] ##STR147## Step 1 ##STR148##
[0314] Compound 20A was prepared from 2-chloro-4,6-dinitrotoluene
(J. Org. Chem., 1985, 50, 1041-1045) as described in U.S. Pat. No.
5,969,155.
[0315] Compound 20A (0.8 g, 4 mmol) in acetone (40 mL) was treated
with 19C (1.74 g, 4.8 mmol) and K.sub.2CO.sub.3 (0.67 g, 4.8 mmol)
and then refluxed for 48 h. Solvent was removed under reduced
pressure and the residue was dissolved in DCM (600 mL) and washed
with water and brine. The organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by chromatography (0.5% MeOH/DCM) to give 20B (1.9 g, 91%)
as yellow solid. .sup.1H NMR (CDCl.sub.3): 8.21 (s, 1H), 8.0 (d,
1H), 7.53 (d, 1H), 7.41 (s, 1H), 7.3-7.0 (15H), 6.75 (s, 1H), 6.65
(d, 1H), 5.26 (s, 2H). Steps 2-3 ##STR149##
[0316] To a stirred solution of compound 20B (1.88 g, 3.62 mmol) in
EtOH (70 mL) was added SnCl.sub.2-2H.sub.2O (3.27 g, 14.48 mmol).
The reaction was refluxed for 3 h and solvent was removed under
reduced pressure. The residue was diluted with sat. NaHCO.sub.3
(120 mL) and extracted with EtOAc (3.times.200 mL). The combined
organic layer was washed with sat. NaHCO.sub.3 and brine; then
dried (Na.sub.2SO.sub.4), filtered and concentrated under to give
1.8 g of crude compound 20C. The crude material can be carried to
the next reaction without further purification. A small portion of
the crude material was purified by flash column chromatography (DCM
containing 2-4% 7N NH.sub.3/MeOH) to give pure compound 20C. MS m/z
247 (MH+).
[0317] To a stirred solution of crude compound 20C (0.6 g, 2.43
mmol) in DCM (10 mL) was added TEA (0.34 mL, 2.46 mmol) and
ClCO.sub.2Me (0.19 mL, 2.43 mmol). The reaction was stirred at RT
overnight and quenched with 2N NaOH (10 mL). Solvent was removed
under reduced pressure and the residue was partitioned between
H.sub.2O and EtOAc. The aqueous layer was extracted with EtOAc
(3.times.30 mL). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(DCM containing 2% 7N NH.sub.3/MeOH). The fraction that contained
the desired product was further purified by preparative TLC (1000
microns) to give pure title compound 20. MS m/z 305 (MH+).
Preparative Example 21
[0318] ##STR150## Step 1 ##STR151##
[0319] Compound 21A was prepared by treating compound 5A with TFA
as described previously Example 1, Step 4.
[0320] A stirred solution of compound 21A (0.5 g, 2.4 mmol) and
compound 21B (0.87 g, 2.4 mmol, Bioconjugate Chem. 2002, 13, 333)
in DMF (25 mL) was treated with HATU (0.95 g, 2.5 mmol) and stirred
overnight. Solvent was removed under high vacuum and water (50 mL)
was added. The mixture was extracted DCM (3.times.50 mL). The
combined organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (10% MeOH/DCM) to give 21C in (1.2 g,
89%). Steps 2-3 ##STR152##
[0321] To a stirred solution of compound 21C (1.2 g, 2.1 mmol) in
THF (50 mL) was added BH.sub.3-THF (2 M, 5 mL). The mixture was
heated at 80.degree. C. for 12 h. The reaction was cooled to RT and
MeOH (15 mL) was added slowly. Solvent was removed under reduced
pressure and the residue was partitioned between EtOAc and water.
The organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure to give 21D (0.85 g, 74%).
[0322] Compound 21D was then hydrogenated at 80.degree. C. for 18 h
in a manner similar to that described in Example 19, Step 3 to
provide the title compound 21. MS m/z 307 (MH+).
Preparative Example 22
[0323] ##STR153## Steps 1-2 ##STR154##
[0324] To compound 6B (0.38 g, 0.84 mmol) in THF at 0.degree. C.
under Ar was added n-BuLi (2.5 M in hexanes, 1.01 mL, 2.53 mmol).
The mixture was stirred at 0.degree. C. for 1 h, and then treated
with MeI (0.052 mL, 0.84 mmol). The reaction was stirred at
0.degree. C. for 1 h, and then treated with saturated aqueous
NH.sub.4Cl. THF was removed under reduced pressure and the aqueous
layer was extracted with EtOAc (3.times.50 mL). The organic layer
was dried (MgSO.sub.4), filtered and concentrated under reduced
pressure. Chromatography (2-2.5% of 7% NH.sub.3-MeOH/DCM) provided
22A (0.179 g, 44%).
[0325] In a manner similar to that found in Example 6, Step 5, 22A
was deprotected to provide the title compound 22. MS m/z 243
(MH+).
Preparative Example 23
[0326] ##STR155## Step 1 ##STR156##
[0327] In a manner similar to that found in Example 4, Step 1, 23A
(Tetrahedron 1967, 23, 3823) was reacted with
4-imidazolecarboxaldehyde to provide 23B. Steps 2-3 ##STR157##
[0328] A solution of 23B (0.050 g, 0.15 mmol) in 1 M NH.sub.3-MeOH
(30 mL) was treated with Raney nickel, hydrogenated (35 psi
H.sub.2) for 2 h, and filtered through celite. Chromatography
(3-15% 7 N NH.sub.3-MeOH/CH.sub.2Cl.sub.2) provided 23C as a yellow
film (0.029 g, 85%). LMCS m/z 271 (MH+).
[0329] In a manner similar to that found in Example 4, Step 3, 23C
was reacted with AcCl to provide the title compound 23. LMCS m/z
229 (MH+).
Preparative Example 24
[0330] ##STR158## Steps 1-2 ##STR159##
[0331] In a manner similar to that found in Example 14 (Step 2) and
Example 4 (Step 1), 6-bromoindole was reduced with NaCNBH.sub.3 and
reacted with 1-tritylimidazole-4-carboxaldehyde to provide 24A.
Steps 3-4 ##STR160##
[0332] A slurry of 24A (0.5 g, 0.96 mmol) in DMSO (5 mL) was
treated with dimethylphosphite (0.2 mL, 2.2 mmol), DIPEA (0.7 mL,
3.8 mmol), 1,4-bis(diphenylphosphino)butane (0.041 g, 0.1 mmol),
and Pd(OAc).sub.2 (0.022 g, 0.1 mmol) and stirred at 100.degree. C.
overnight. The reaction was poured on water and extracted with
EtOAc (3.times.). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated. Chromatography
(0-100% EtOAc/hexanes) provided 24B as a light yellow solid (0.081
g, 15%).
[0333] In a manner similar to that found in Example 6, Step 5, 24B
was deprotected to provide the title compound 24. LMCS m/z 308
(MH+).
Preparative Example 25
[0334] ##STR161##
[0335] To a well-stirred mixture of Compound 10 (0.24 g, 0.87 mmol)
in 1:1 THF--H.sub.2O (10 mL) was added phenyl chloroformate (0.29
mL, 2.3 mmol) dropwise. The reaction was stirred at 20.degree. C.
for 4 h and then diluted with EtOAc. The organic layer was
isolated, dried over Na.sub.2SO.sub.4 and concentrated. The
resulting residue was dissolved in MeOH, treated with Et.sub.3N
(0.6 mL, 4.3 mmol), and stirred overnight. The solution was
concentrated and subjected to chromatography (0-20% 1 N
NH.sub.3-MeOH/EtOAc) to provide the title compound 25 as a pale
yellow solid (0.079 g, 87%). LMCS m/z 294 (MH+).
Preparative Example 26
[0336] ##STR162##
[0337] In a manner similar to that found in Example 25, 10 was
treated with phenyl chlorothionoformate to give Compound 26. LMCS
m/z 310 (MH+).
Preparative Example 27
[0338] ##STR163## Step 1 ##STR164##
[0339] A solution of 2-methoxy-5-nitroaniline (14.4 g, 85 mmol) in
CH.sub.2Cl.sub.2 (100 mL) was treated with ClCO.sub.2Me (8.0 mL,
103 mmol) and Et.sub.3N (17.9 mL, 128 mmol), stirred overnight at
20.degree. C., and concentrated. Chromatography (20-40%
EtOAc/hexanes) provided 27A as a yellow solid (9.21 g, 48%). Step 2
##STR165##
[0340] In a manner similar to that found in Example 6, Step 2, 27A
was hydrogenated to provide 27B. Step 3 ##STR166##
[0341] A solution of 27B (7.8 g, 40 mmol) in EtOH (100 mL) was
treated with bromoacetaldehyde diethyl acetal (6.7 mL, 44 mmol) and
NaHCO.sub.3 (3.4 g, 40 mmol) and heated to reflux for 3 d. The
reaction was concentrated, taken up in Et.sub.2O, and washed with
water. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. Chromatography (0-40% EtOAc/hexanes) provided 27C
(6.4 g, 51%). Step 4 ##STR167##
[0342] A solution of 27C (5.3 g, 17 mmol) in TFA (70 mL) was
treated with trifluoroacetic anhydride (90 mL) and heated to reflux
overnight. The reaction was concentrated and subjected to
chromatography (0-40% EtOAc/hexanes) to provide 27D (2.9 g, 55%) as
a pale yellow solid. Steps 5-7 ##STR168##
[0343] A mixture of 27D (2.9 g, 9.2 mmol) in MeOH (20 mL) was
treated with saturated aqueous Na.sub.2CO.sub.3 (5 mL) and heated
at 55.degree. C. for 1 d. The reaction was concentrated, extracted
with CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4 and
concentrated. Chromatography (20-40% EtOAc/hexanes) provided 27E
(1.6 g, 78%).
[0344] In a manner similar to that found in Example 14, Step 2, and
Example 4, Step 1, 27E was reduced with NaCNBH.sub.3 and then
converted to the title compound 27. LMCS m/z 303 (MH+).
Preparative Example 28
[0345] ##STR169## Step 1 ##STR170##
[0346] A solution of 2-methoxy-5-nitroaniline (10.8 g, 64 mmol) and
DMS (10.6 mL, 96 mmol) in CH.sub.3CN (100 mL) was treated slowly
with isoamyl nitrite (10.3 mL, 77 mmol) and then heated at
45.degree. C. for 1 h. The reaction was concentrated and subjected
to chromatography (10% EtOAc/hexanes) to provide 28A (9.1 g, 71%).
Steps 2-4 ##STR171##
[0347] In a manner similar to that found in Example 27, Steps 2-4,
28A was hydrogenated, alkylated and cyclized to provide 28B. Steps
5-8 ##STR172##
[0348] A solution of 28B (3.16 g, 11 mmol) in CH.sub.2Cl.sub.2 (50
mL) was treated with urea-hydrogen peroxide (10.3 g, 109 mmol) and
K.sub.2HPO.sub.4 (17.1 g, 98 mmol) and stirred 0.5 h.
Trifluoroacetic anhydride (3.8 mL, 28 mmol) was then added slowly.
The reaction mixture was stirred overnight at 20.degree. C. and
filtered through a celite pad. Chromatography (0-40% EtOAc/hexanes)
provided 28C (1.5 g, 43%).
[0349] In a manner similar to that found in Example 27, Steps 5-7,
28C was deprotected, reduced, and then converted to title compound
28. LMCS m/z 292 (MH+).
Preparative Example 29
[0350] ##STR173## Step 1 ##STR174##
[0351] A suspension of 4-hydroxymethylimidazole (15 g, 111 mmol) in
toluene (100 mL) was treated slowly with a solution of SOCl.sub.2
(8 mL, 144 mmol) in toluene (10 mL) via an addition funnel. The
mixture was then refluxed for 1.5 h, cooled, and concentrated to
provide 29B as a gray solid (15.8 g, 93%). Steps 2-3 ##STR175##
[0352] A mixture of 6-nitroindole (3.5 g, 21.8 mmol) in DMF was
treated with 60% NaH (1.3 g, 32.7 mmol), stirred 30 min at
20.degree. C., and treated with 29B (4.0 g, 26.2 mmol). The mixture
was heated at 70.degree. C. overnight, filtered through celite and
concentrated. Chromatography (0-7% 1 N NH.sub.3-MeOH/EtOAc)
provided 29C as a yellow solid (1.7 g, 32%).
[0353] A solution of 29C (0.46 g, 1.9 mmol) in EtOH was treated
with Raney nickel and hydrogenated (1 atm H.sub.2) overnight. The
mixture was filtered through celite, and concentrated to provide
Compound 29 as a gray solid (0.39 g, 98%). LMCS m/z 213 (MH+).
Preparative Example 30
[0354] ##STR176##
[0355] In a manner similar to that found in Example 27, Step 1, 29
was reacted with ClCO.sub.2Me to provide 30. LMCS m/z 271
(MH+).
Preparative Example 31
[0356] ##STR177## Steps 1-2 ##STR178##
[0357] A solution of 29B (6.9 g, 45.4 mmol) in DMF (100 mL) was
treated with 5-nitroindole (14.7 g, 90.8 mmol) and KF (50% wt on
celite, 15.8 g, 136 mmol) and heated at 90.degree. C. overnight.
The mixture was filtered through celite, and concentrated.
Chromatography (0-10% 1 N NH.sub.3-MeOH/EtOAc) provided 31A as a
yellow solid (3.72 g, 34%).
[0358] In a manner similar to that found in Example 29, Step 3, 31A
was hydrogenated to Compound 31. LMCS m/z 213 (MH+).
Preparative Example 32
[0359] ##STR179##
[0360] In a manner similar to that found in Example 27, Step 1, 31
was reacted with ClCO.sub.2Me to provide 32. LMCS m/z 271
(MH+).
Preparative Example 33
[0361] ##STR180##
[0362] In a manner similar to that found in Example 14, Step 2, 32
was reduced with NaCNBH.sub.3 to give 33. LMCS m/z 273 (MH+).
Preparative Example 34
[0363] ##STR181##
[0364] In a manner similar to that found in Example 31, Step 1 and
Example 29, Step 3, N-methyl-5-nitroindole (Organic Process
Research & Development 2001, 5, 604) was alkylated with 29B and
hydrogenated to provide Compound 34. LMCS m/z 227 (MH+).
Preparative Example 35
[0365] ##STR182## Steps 1-3 ##STR183##
[0366] In a manner similar to that found in Example 14 (Step 2),
Example 4 (Step 1), and Example 6 (Step 2), 6-benzyloxyindole was
reduced with NaCNBH.sub.3, reacted with 4-imidazolecarboxaldehyde
and hydrogenated to provide 35A.
Step 4
[0367] A solution of 35A (0.12 g, 0.46 mmol) and Et.sub.3N (0.20
mL, 1.12 mmol) in dichloroethane (10 mL) was treated dropwise with
MeNCO (0.035 g, 0.61 mmol) and refluxed for 2 h. The reaction was
then stirred overnight at 20.degree. C. and concentrated. The
material was treated with water and extracted with CH.sub.2Cl.sub.2
(3.times.). The combined organic layers were then concentrated. The
residue was taken up in Et.sub.2NH (1.5 mL) and stirred overnight.
The reaction was treated with water and extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic layers were then
concentrated and subjected to chromatography (2-5%
MeOH/CH.sub.2Cl.sub.2) to provide 35 as a white foam (0.015 g,
10%). LMCS m/z 273 (MH+).
Preparative Example 36
[0368] ##STR184##
[0369] In a manner similar to that found in Example 4 (Step 1),
Example 29 (Step 3), and Example 27 (Step 1),
7-nitro-1,2,3,4-tetrahydroquinoline (U.S. Pat. No. 5,283,336, 1994)
was reacted with 4-imidazolecarboxaldehyde, hydrogenated, and then
treated with ClCO.sub.2Me to provide 36. LMCS m/z 287 (MH+).
Preparative Example 37
[0370] ##STR185## Steps 1-3 ##STR186##
[0371] In a manner similar to that found in Example 1 (Step 1),
Example 29 (Step 3), and Example 5 (Step 1),
7-nitro-1,2,3,4-tetrahydroquinoline (U.S. Pat. No. 5,283,336, 1994)
was treated with (BOC).sub.2O/DMAP, hydrogenated, and then reacted
with methanesulfonic anhydride/Et.sub.3N to provide 37A. Steps 4-5
##STR187##
[0372] A solution of 37C (0.49 g, 1.5 mmol) in CH.sub.2Cl.sub.2 (20
mL) was treated with 4 M HCl-dioxane (10 mL), stirred 1 h at
20.degree. C., and concentrated. The mixture was dissolved in MeOH
(10 mL), treated with dimethylaminomethyl-polystrene resin, and
stirred at 20.degree. C. for 1 h. The mixture was filtered and
concentrated to provide 37D as a yellow gum (0.33 g, 97%). In a
manner similar to that found in Example 4, Step 1, 37D was reacted
with 4-imidazolecarboxyaldehyde to provide the title compound 37.
LMCS m/z 307 (MH+).
Preparative Example 38
[0373] ##STR188## Step 1 ##STR189##
[0374] To a stirred solution of 7-methoxyindole (3 g, 20.4 mmol) in
THF (80 mL) was added toluenesulfonyl chloride (4 g, 21 mmol) and
NaH (60%, 1.22 g). The mixture was stirred at RT overnight,
quenched with water, and concentrated under reduced pressure. The
residue was partitioned between water (100 mL) and EtOAc (100 mL).
The organic layer was then dried (Na.sub.2SO.sub.4), filtered and
concentrated to provide 38A (1.5 g, 24%). Step 2 ##STR190##
[0375] To a stirred solution of 38A in DCM (35 mL) was added
HNO.sub.3/SiO.sub.2 (17 g, J. Org. Chem. 1993, 58, 1666). The
mixture was sonicated for 10 minutes, and stirred at room
temperature for 1.5 h. The reaction was filtered and concentrated.
Column chromatography (10-40% EtOAc/Hexane) provided 38B (0.49 g,
29%). Steps 3-4 ##STR191##
[0376] In a manner similar to that found in Example 1 (Step 2) and
Example 15 (Step 3), 38B was hydrogenated and then reacted with
ClCO.sub.2Me to provide 38C. Step 5-7 ##STR192##
[0377] To a stirred solution of 38C (0.42 g, 1.14 mmol) in MeOH (14
mL) was added Mg powder (0.14 g, 5.7 mmol). The resulting
suspension was sonicated for 20 minutes, and the reaction was
monitored by TLC. After the disappearance of starting material,
solvent was removed under reduced pressure. The residue was
partitioned between DCM (50 mL) and 0.5 N HCl (40 mL). The organic
phase was washed by NaHCO.sub.3 (40 mL) and brine (40 mL), dried
(MgSO.sub.4), filtered and concentrated to provide 38D (0.23 g,
92%).
[0378] In a manner similar to that found in Example 14 (Step 2) and
Example 4 (Step 1), 38D was reduced with NaCNBH.sub.3/AcOH and
treated with imidazole-4-carboxaldehyde to provide the title
compound 38. MS m/z 303 (MH+).
Preparative Example 39
[0379] ##STR193## Step 1 ##STR194##
[0380] In a manner similar to that found in Example 38 (Step 1),
20A was treated with toluenesulfonyl chloride and NaH to provide
compound 39A. Step 2 ##STR195##
[0381] A solution of compound 39A (4.56 g, 13 mmol) in EtOH (260
mL) was treated with SnCl.sub.2-2H.sub.2O (11.7 g, 52 mmol). The
reaction was refluxed at 90.degree. C. for 3 h and then
concentrated. The residue was diluted with sat. aq. NaHCO.sub.3
(100 mL) and extracted with EtOAc (2.times.150 mL). The combined
organic layer was dried (Na.sub.2SO.sub.4), filtered and evaporated
to give a brown solid 39B. Steps 3-5 ##STR196##
[0382] In a manner similar to that found in Example 7 (Steps 1-3),
39B was treated with Ac.sub.2O/HCO.sub.2H, reduced with
BH.sub.3--SMe.sub.2, and treated with MeNCO to yield compound 39C.
Steps 6-8 ##STR197##
[0383] A solution of 39C (2.7 g, 7.0 mmol) in MeOH (100 mL) was
treated with KOH (5 g), stirred at RT for 1 h, and concentrated.
The mixture was then treated with water and extracted with EtOAc
(3.times.50 mL). The combined organic layer was dried
(Na.sub.2SO.sub.4), filtered and evaporated to provide 39D.
[0384] In a manner similar to that previously described, 39D was
reduced with NaBH.sub.3CN (Example 14, Step 2, AcOH used as
solvent) and then treated with 4-imadzolecarboxaldehyde (Example 4,
Step 1) to give the title compound 39. MS m/z 320 (MH+).
Preparative Example 40
[0385] ##STR198##
[0386] A mixture of 10A (0.25 g, 1.3 mmol) and
imidazole-4-carboxaldehyde (1B, 0.16 g, 1.7 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was treated with Ti(OiPr).sub.4 (0.75 mL,
2.6 mmol), stirred at 20.degree. C. overnight, and then treated
with Et.sub.2AlCN (2.6 mL, 1 M/toluene). After 18 h, EtOAc,
H.sub.2O, and celite were added. Filtration and subsequent
chromatography (0-10% of 7N NH.sub.3-MeOH in CH.sub.2Cl.sub.2)
provided 40 as a yellow solid (0.07 g, 18%). LCMS m/z 303
(MH+).
Preparative Example 41
[0387] ##STR199## Steps 1-2 ##STR200##
[0388] A mixture of 3-methoxylpropionic acid (0.03 mL, 0.32 mmol)
in DMF (4 mL) was treated with EDCI (61 mg, 0.32 mmol) and HOBt (43
mg, 0.32 mmol). After stirring for 10 min, compound 41A (100 mg,
0.21 mmol, see Example 6, Step 4) was added. The reaction was
stirred at RT overnight, diluted with NaHCO.sub.3 (50 mL), and
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined
organic layer was washed with H.sub.2O (2.times.60 mL), dried over
Na.sub.2SO.sub.4 and concentrated to provide 41B.
[0389] In a manner similar to that found in Example 6 (Step 5), 41B
was treated with TFA and Et.sub.3SiH to provide the title compound
41. LCMS m/z 315 (MH+).
Preparative Example 42
[0390] ##STR201## Steps 1-2 ##STR202##
[0391] In a manner similar to that found in Example 41, 42A
(Boc-Nle-OH) was coupled with 41A to afford 42B Global deprotection
(TFA/Et.sub.3SiH) and chromatography (reverse-phase HPLC, 0-15%
gradient of 0.25% NH.sub.3-MeOH/H.sub.2O and 0.25%
NH.sub.3-MeOH/acetonitrile) provided the title compound 42. LCMS
m/z 342 (MH+).
Preparative Example 43
[0392] ##STR203## Steps 1-3 ##STR204##
[0393] In a manner similar to that found in Example 7, 7B was
sequentially treated with acetoxyacetyl chloride, TFA, and then
4-imidazolecarboxaldehyde to provide 43A. MS m/z 329 (MH+).
Step 4
[0394] A mixture of the ester 43A (180 mg, 0.55 mmol) in methanol
(20 mL) was treated with LiOH (200 mg), stirred for 1 h at
25.degree. C., and then concentrated. Chromatography (DCM
containing 5% of 7N NH.sub.3/MeOH) provided the title compound 43
(80 mg, 51%). MS m/z 287 (MH+).
Preparative Example 44
[0395] ##STR205## Steps 1-2 ##STR206##
[0396] In a manner similar to that found in Example 7, 1A was
acylated with acetic anhydride/pyridine and then reduced with
BH.sub.3--SMe.sub.2 to provide 44A.
Steps 3-5
[0397] In a manner similar to that found in Example 7, 44A was
treated with ClCO.sub.2Me/pyridine and then converted to the title
compound 44. MS m/z 301 (MH+).
Preparative Example 45
[0398] ##STR207## Step 1 ##STR208##
[0399] A mixture of 44A (100 mg, 0.38 mmol), Et.sub.3N (0.11 mL,
0.76 mmol) and carbonyldiimidazole (92 mg, 0.38 mmol) in DCM (5 mL)
was stirred overnight. Additional Et.sub.3N (0.2 mL, 1.43 mmol) and
carbonyldiimidazole (0.2 g, 1.2 mmol) was then added. After 18 h,
the reaction was concentrated and chromatographed (50-80%
EtOAc/hexanes) to give 45A (155 mg). Steps 2-4 ##STR209##
[0400] Compound 45A was mixed with CH.sub.3CN (5 mL) and MeI (3 mL,
48 mmol) in a sealed tube and heated at 55.degree. C. for 3 h.
Solvent was removed and the residue was dried under high vacuum for
0.5 h. THF (5 mL), MeONH.sub.2--HCl (95 mg, 1.14 mmol) and DIPEA
(0.2 mL, 1.14 mmol) were sequentially added. The reaction was
stirred for 2 d, concentrated, and then partitioned between water
and DCM. The organic layer was dried (Na.sub.2SO.sub.4), filtered
and evaporated. Chromatography (50-60% EtOAc/hexanes) gave 45B (100
mg).
[0401] In a manner similar to that found in Example 1 (Step 4) and
Example 4, (Step 1), compound 45B was deprotected and converted to
the title compound 45. MS m/z 316 (MH+).
Preparative Example 46
[0402] ##STR210## Step 1 ##STR211##
[0403] A 1 L 3-neck round-bottom flask equipped with a condenser
and a thermometer was charged with 2,4-dinitrotoluene (46A, 20 g,
0.11 mol), concentrated sulfuric acid (50 mL), water (50 mL) and
pre-made K.sub.2SO.sub.4 (KOH+conc. H.sub.2SO.sub.4, equivalent to
100 mg of K.sub.2SO.sub.4). The mixture was heated to 80.degree. C.
to 90.degree. C. and treated with NaBrO.sub.3 (17.24 g, 0.114 mol)
in portions, while maintaining a temperature of 80.degree. C. to
90.degree. C. The mixture was then stirred at 85.degree. C.
overnight, cooled to RT and extracted with EtOAc (3.times.200 mL).
The combined organic layers were washed with sat. aq. NaHCO.sub.3
and brine solution. The organic layer was dried (MgSO.sub.4),
filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography (2-5% EtOAc/hexanes) to
give 46B (8.02 g, 28%). Step 2 ##STR212##
[0404] To compound 46B (13.86 g, 53.3 mmol) was added
N,N-dimethylformamide dimethyl acetal (79.5 mL, 533 mmol). The
reaction was heated to reflux at 115.degree. C. The mixture then
was cooled and concentrated. The crude product was dissolved in
MeOH (250 mL), treated with HCl (10.5 mL), and refluxed for 4 h.
The reaction was cooled to RT, diluted with water and extracted
with EtOAc (3.times.100 mL). The combined organic layers were dried
(MgSO.sub.4), filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography (2.5-8%
EtOAc/hexanes) to give compound 46C (14.67 g, 82%). Step 3
##STR213##
[0405] To a solution of 46C (4.04 g, 12.1 mmol) in glacial AcOH (40
mL) at 60.degree. C. was added iron powder (2.03 g, 36.3 mmol). The
reaction was heated to 110.degree. C. and stirred for 40 min. Then
the mixture was cooled and poured into cold water and the
precipitate was filtered. The filtrate was extracted with EtOAc
(3.times.50 mL). The combined organic layers were dried
(MgSO.sub.4), filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography (5-15%
EtOAc/hexanes) to give 46D (0.93 g, 32%). Steps 4-5 ##STR214##
[0406] In a manner similar to that described in previous examples,
46D was protected with TsCl (Example 38, Step 1) and reduced with
SnCl.sub.2-2H.sub.2O (Example 39, Step 2) to provide 46E. Steps
6-11 ##STR215##
[0407] In a manner similar to that described in Example 7, 46E was
treated with Ac.sub.2O/HCO.sub.2H, reduced with BH.sub.3, and
treated with ClCO.sub.2Me/pyridine to provide 46F.
[0408] Compound 46F was then deprotected with Mg (Example 38, Step
5), reduced with NaBH.sub.3CN (Example 14, Step 2, AcOH used as
solvent), and treated with 4-imidazolecarboxaldehyde (Example 4,
Step 1) to provide 46. MS m/z 365 (MH+).
Preparative Example 47
[0409] ##STR216## Steps 1-4 ##STR217##
[0410] A mixture of 46F (121 mg, 0.28 mmol) in anhydrous THF at
-78.degree. C. under argon was treated with n-BuLi (1.6 M in
hexanes, 0.17 mL, 0.28 mmol) dropwise, stirred at -78.degree. C.
for 8 min and then treated with N-fluorobenzenesulfonimide (87 mg,
0.28 mmol, solution in THF, added via cannula). The mixture was
allowed to warm to 0.degree. C. over 2 h, quenched with water, and
extracted with EtOAc (3.times.10 mL). The combined organic layer
was dried (MgSO.sub.4), filtered and concentrated. The residue was
purified by flash column chromatography (0-25% EtOAc/hexanes) to
give compound 47A (62 mg, 59%).
[0411] In a manner similar to that found in previous examples, 47A
was deprotected with KOH (Example 39, Step 6), reduced with
NaBH.sub.3CN (Example 14, Step 2, AcOH used as solvent), and
treated with 4-imidazolecarboxaldehyde (Example 4, Step 1) to give
compound 47. MS m/z 305 (MH+).
Preparative Example 48
[0412] ##STR218## Step 1 ##STR219##
[0413] In a manner similar to that found in Example 7, compound 46E
was treated with ClCO.sub.2Me/DIPEA to provide 48A. Steps 2-5
##STR220##
[0414] A mixture of intermediate 48A (500 mg, 1.2 mmol),
Zn(CN).sub.2 (160 mg, 1.3 mmol),
1,1'-bis(diphenylphosphino)ferrocene (275 mg, 0.3 mmol), and
Pd.sub.2 dba.sub.3 (55 mg, 0.1 mmol) was stirred in DMF (100 mL) at
25.degree. C. under a N.sub.2 atmosphere and then heated at
120.degree. C. for 12 h. The suspension was cooled to RT and
concentrated. The residue was partitioned between EtOAc
(3.times.100 mL) and sat. aq. NH.sub.4Cl (50 mL). The combined
organic phase was dried over Na.sub.2SO.sub.4 and concentrated.
Column chromatography (DCM) provided 48B (415 mg, 94%).
[0415] In a manner similar to that previously described, 48B was
deprotected with KOH (Example 39, Step 6), reduced with
NaBH.sub.3CN (Example 14, Step 2, AcOH used as solvent) and treated
with 4-imidazolecarboxaldehyde (Example 4, Step 1) to give the
title compound 48. MS m/z 298.4 (MH+).
Preparative Example 49
[0416] ##STR221## Step 1 ##STR222##
[0417] A stirred solution of methyl 6-aminoindole-4-carboxylate
(49A, 0.5 g, 2.63 mmol) in THF (10 mL) under Ar at 0.degree. C. was
treated sequentially with NaH (0.095 g, 3.95 mmol, added
portionwise) and TsCl (0.551 g, 3.16 mmol, added portionwise) and
then allowed to warm to RT. After 2 h, the reaction was quenched
with MeOH (3.95 mmol) at 0.degree. C., poured onto ice cold water
(10 mL) and extracted with EtOAc. The organic layer was washed with
brine, dried over (Na.sub.2SO.sub.4), filtered and concentrated.
Chromatography (40% EtOAc/hexanes) afforded 49B (0.51 g, 57%).
Steps 2-5 ##STR223##
[0418] In a manner similar to that found in Example 7, compound 49B
was treated with ClCO.sub.2Me/pyridine. The product (0.45 g, 1.12
mmol) was taken up in DMF (5 mL) and treated with LiOH (0.110 g,
4.48 mmol). After 10 min, thioglycolic acid (0.124 g, 1.34 mmol)
was added. The resulting solution was stirred at RT for 48 h,
diluted with EtOAc and washed with water. After extracting the
water layer with EtOAc, the combined organic layers were washed
with sat. aq. Na.sub.2CO.sub.3 (2.times.), dried over sodium
sulfate, filtered and evaporated. Chromatography (50%
EtOAc/hexanes) afforded 49C (0.15 g, 54%).
[0419] In a manner similar to that previously described, 49C was
reduced with NaBH.sub.3CN (Example 14, Step 2, AcOH used solvent)
and treated with 4-imidazolecarboxaldehyde (Example 4, Step 1) to
give compound 49. MS m/z 331 (MH+).
Preparative Example 50
[0420] ##STR224## Step 1 ##STR225##
[0421] In a manner similar to that found in Example 14 (Step 2),
compound 49C reduced with NaBH.sub.3CN. A solution of the product
(0.060 g, 0.24 mmol) in THF was treated with LAH (0.027 g, 0.72
mmol) at 0.degree. C. under Ar. After 2 h at RT, the reaction was
quenched with saturated Na.sub.2SO.sub.4 and filtered. The
precipitate was washed with ethyl acetate (50 mL). The organic
layer was washed with brine and concentrated. Chromatography (2% 7N
NH.sub.3-MeOH in DCM) gave 50A (0.030 g, 57%).
[0422] In a manner as described in Example 4 (Step 1), 50A was
converted to the title compound 50. MS m/z 303 (MH+).
Preparative Example 51
[0423] ##STR226## Step 1 ##STR227##
[0424] In a manner similar to that found in Example 45 (Step 1), 7B
was treated with carbonyldiimidazole to provide compound 51A. Steps
2-4 ##STR228##
[0425] A solution of pyridine-2-methanol (145 .mu.L, 1.5 mmol) in
THF (5 mL) at 20.degree. C. was treated with NaHMDS (300 .mu.L, 1.5
mmol), stirred for 1 h, and then treated with 51A (100 mg, 0.3
mmol). After stirring overnight, the solution was diluted with
saturated aqueous NaHCO.sub.3 (10 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL). The combined organic phase was
concentrated in vacuo to provide 51B.
[0426] In a manner similar to that found in Example 1 (Step 4) and
Example 4 (Step 1), 51B was deprotected with TFA and converted to
the title compound 51 LCMS m/z 364 (MH+).
Preparative Example 52
[0427] ##STR229## Step 1 ##STR230##
[0428] A solution of 4-(methylsulfonyl)benzyl alcohol (52A, 123 mg,
0.66 mmol) in THF (3 mL) was treated with 4-nitrophenyl
chloroformate (133 mg, 0.66 mmol) and pyridine (54 .mu.L, 0.66
mmol). The mixture was stirred 4 h at 20.degree. C. and then
partitioned between EtOAc and water. The organic layer was washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated to provide
52B. Steps 2-3 ##STR231##
[0429] A solution of 52B (300 mg, crude material from previous
step) in THF (3 mL) was treated with 6B (180 mg, 0.39 mmol) and
pyridine (100 .mu.L, 1.24 mmol). After stirring for 2 d at
20.degree. C., the mixture was diluted with CH.sub.2Cl.sub.2,
washed with saturated aqueous NaHCO.sub.3, and concentrated to
provide 52C.
[0430] This product was then deprotected with TFA to provide the
title compound 52 in a manner similar to that found in Example 6
(Step 5). LCMS m/z 427 (MH+).
Preparative Example 53
[0431] ##STR232## Step 1 ##STR233##
[0432] A stirred solution of aniline 53A (0.44 g, 2.47 mmol) in
CH.sub.2Cl.sub.2 (25 mL) at -78.degree. C. was sequentially treated
with acetyl aldehyde (1.0 M solution in CH.sub.2Cl.sub.2, 2.7 mL),
NaBH(OAc).sub.3 (0.6 g, 2.85 mmol) and AcOH (one drop). The
reaction was allowed to warm to 0.degree. C. over a 4.5 h, quenched
with H.sub.2O and then extracted with CH.sub.2Cl.sub.2 (3.times.40
mL). The combined organic extracts were washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated. Chromatography (PTLC, 30:1
CH.sub.2Cl.sub.2-MeOH) afforded 53B (0.295 g). Steps 2-5
##STR234##
[0433] In a manner similar to that found in Example 7 (Step 3 and
Step 2), 53B was treated with MeNCO and reduced with
BH.sub.3--SMe.sub.2 to afford 53C.
[0434] In a manner similar to that found in Example 4 (Step 1) and
Example 6 (Step 5), 53C was treated with
1-tritylimidazole-4-carboxaldehyde and then deprotected with
TFA/EtSiH.sub.3 to afford the title compound 53. LCMS m/z 328
(MH+).
[0435] Compound 53D was synthesized following the procedures set
forth above, except using aqueous formaldehyde in Step 1. LCMS m/z
314 (MH+). ##STR235##
Preparative Example 54
[0436] ##STR236## Steps 1-3 ##STR237##
[0437] In a manner similar to that found in Example 7 (Step 2), 53A
was reduced with BH.sub.3--SMe.sub.2. The product (0.1 g, 0.62
mmol) was dissolved in CH.sub.2Cl.sub.2 (5 mL), and treated with
Et.sub.3N (0.22 mL, 1.58 mmol) and ClCO.sub.2Me (0.07 mL, 0.91
mmol). The mixture was stirred at RT for 4 h, and then diluted with
CH.sub.2Cl.sub.2 (50 mL). The organic solution was washed with
H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and concentrated.
Chromatography (PTLC, 25:1 CH.sub.2Cl.sub.2-MeOH) afforded 54A (46
mg, 34%).
[0438] In a manner similar to that found in Example 4 (Step 1), 54A
was treated with imidazole-4-carboxaldehyde and catalytic p-toluene
sulfonic acid to afford the title compound 55 as a yellow solid.
LCMS m/z 301 (MH+).
[0439] Compound 54B was synthesized following the procedures set
forth above, except using MeNCO in Step 2. LCMS m/z 300 (MH+).
##STR238##
[0440] The following compounds were prepared following essentially
the same procedures as in the examples above. TABLE-US-00009 MS Cpd
Structure (MH+) 100 ##STR239## 215 101 ##STR240## 257 102
##STR241## 286 103 ##STR242## 274 104 ##STR243## 307 105 ##STR244##
307 106 ##STR245## 307 107 ##STR246## 292 108 ##STR247## 292 109
##STR248## 292 110 ##STR249## 292 111 ##STR250## 256 112 ##STR251##
255 113 ##STR252## 255 114 ##STR253## 285 115 ##STR254## 291 116
##STR255## 276 117 ##STR256## 256 118 ##STR257## 255 119 ##STR258##
269 120 ##STR259## 285 121 ##STR260## 285 122 ##STR261## 299 123
##STR262## 291 124 ##STR263## 305 125 ##STR264## 271 126 ##STR265##
283 127 ##STR266## 258 127 ##STR267## 321 128 ##STR268## 302 129
##STR269## 301 130 ##STR270## 314 131 ##STR271## 300 132 ##STR272##
357 133 ##STR273## 343 134 ##STR274## 385 135 ##STR275## 329 136
##STR276## 331 137 ##STR277## 317 138 ##STR278## 407 139 ##STR279##
349 140 ##STR280## 363 141 ##STR281## 349 142 ##STR282## 325 143
##STR283## 311 144 ##STR284## 325 145 ##STR285## 331 146 ##STR286##
345 147 ##STR287## 363 148 ##STR288## 399 149 ##STR289## 391 150
##STR290## 369 151 ##STR291## 353 152 ##STR292## 373 153 ##STR293##
361 154 ##STR294## 363 155 ##STR295## 379 156 ##STR296## 377 157
##STR297## 389 158 ##STR298## 375 159 ##STR299## 342 160 ##STR300##
360 161 ##STR301## 317 162 ##STR302## 367 163 ##STR303## 356 164
##STR304## 362 165 ##STR305## 390 166 ##STR306## 371 167 ##STR307##
795036 168 ##STR308## 307 169 ##STR309## 321 170 ##STR310## 335 171
##STR311## 335 172 ##STR312## 327 173 ##STR313## 341 174 ##STR314##
334 175 ##STR315## 336 176 ##STR316## 364 177 ##STR317## 309 178
##STR318## 357 179 ##STR319## 315 180 ##STR320## 343 181 ##STR321##
301 182 ##STR322## 334 183 ##STR323## 334 184 ##STR324## 339 185
##STR325## 285 186 ##STR326## 300 187 ##STR327## 315 188 ##STR328##
343 189 ##STR329## 301 190 ##STR330## 305 191 ##STR331## 286 192
##STR332## 301 193 ##STR333## 300 194 ##STR334## 381 195 ##STR335##
341 196 ##STR336## 321 197 ##STR337## 314 198 ##STR338## 345 199
##STR339## 312 200 ##STR340## 365 201 ##STR341## 305 202 ##STR342##
371 203 ##STR343## 339 204 ##STR344## 345 205 ##STR345## 359 206
##STR346## 405 207 ##STR347## 452 208 ##STR348## 319 209 ##STR349##
307 210 ##STR350## 393 211 ##STR351## 329 212 ##STR352## 329 213
##STR353## 343 214 ##STR354## 370 215 ##STR355## 392 216 ##STR356##
392 217 ##STR357## 392 218 ##STR358## 334 219 ##STR359## 352
220 ##STR360## 364 221 ##STR361## 348 222 ##STR362## 366 223
##STR363## 378 224 ##STR364## 362 225 ##STR365## 376 226 ##STR366##
390 227 ##STR367## 368 228 ##STR368## 338 229 ##STR369## 415 230
##STR370## 364 231 ##STR371## 364 232 ##STR372## 380 233 ##STR373##
380 234 ##STR374## 392 235 ##STR375## 362 236 ##STR376## 368 237
##STR377## 376 238 ##STR378## 394 239 ##STR379## 394 240 ##STR380##
406 241 ##STR381## 390 242 ##STR382## 404 243 ##STR383## 396 244
##STR384## 366 245 ##STR385## 340 246 ##STR386## 422 247 ##STR387##
431 248 ##STR388## 378 249 ##STR389## 431 250 ##STR390## 352 251
##STR391## 333 252 ##STR392## 365 253 ##STR393## 387 254 ##STR394##
367 255 ##STR395## 341 256 ##STR396## 325 257 ##STR397## 331 258
##STR398## 363 259 ##STR399## 362 260 ##STR400## 380 261 ##STR401##
380 262 ##STR402## 347 263 ##STR403## 345 264 ##STR404## 326 265
##STR405## 379 266 ##STR406## 381 267 ##STR407## 381 268 ##STR408##
341 269 ##STR409## 441 270 ##STR410## 401 271 ##STR411## 381
Assay:
[0441] Efficacy agonist activity values (Emax, GTP.gamma.S assay)
for .alpha.2A and .alpha.2C were determined by following the
general procedure detailed by Umland et. al ("Receptor reserve
analysis of the human .alpha..sub.2c-adrenoceptor using
[.sup.35S]GTP.gamma.S and cAMP functional assays" European Journal
of Pharmacology 2001, 411, 211-221). For the purposes of the
present invention, a compound is defined to be a specific or at
least selective agonist of the .alpha.2C receptor subtype if the
compound's efficacy at the .alpha.2C receptor is .gtoreq.30% Emax
(GTP.gamma.S assay) and it's efficacy at the .alpha.2A receptor is
.gtoreq.30% Emax (GTP.gamma.S assay).
[0442] The following compounds were evaluated to be specific or at
least selective agonists of the .alpha.2C receptor subtype based on
the previously defined definition: 1G, 1H, 11, 2G, 3, 5C, 5D, 6, 7,
7D, 7F, 7G, 7H, 7I, 7N, 10, 11, 11C, 12, 12B, 12D, 14, 15, 17B, 21,
23C, 30, 32, 39, 43, 45, 46, 113, 114, 115, 120, 122, 123, 124,
125, 127A, 128, 129, 132, 136, 137, 142, 143, 146, 151, 168, 169,
170, 171, 174, 175, 176, 185, 186, 187, 198, 236, 244, 250, and
266.
[0443] While the present invention has been described with in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *